Hypertension was present in 227/358 (63.4%) children at presentation of whom 171/227 (47.8%) required treatment with antihypertensive drugs for at least 6 weeks. Diuretics were used for symptomatic management of oedema and were often used as a first line antihypertensive drug in children considered to have volume overload. Of those with persistent hypertension 146/171 (85.4%) received an ACE-inhibitor as the preferred antihypertensive drug. Overall 213/358 (59.5%) received an ACE-inhibitor for its antiproteinuric effect. Renal function and s-potassium were monitored in all children who were treated with an ACE-inhibitor. No child experienced an allergic response or developed significant coughing with this treatment. An acute increase in s-creatinine levels occurred in some patients, usually in association with volume contraction, which was reversible in all cases with fluid resuscitation.

The mean s-albumin level at the time of presentation was 13.2 5.2 g/L. Some patients had below detectable s-albumin levels and for these the lowest value documented was an arbitrary level of 10g/L for the purpose of statistical analysis. This means that the true mean level was in fact lower. The mean s-cholesterol at the time of presentation was 11.4 7.3 mmol/L. As already stated above, statins were only prescribed to a limited number of older children with persistent hypercholesterolaemia. The main reason why younger children with similar high cholesterol levels were not treated with statins is the lack of long-term safety information on the effects of these drugs on the developing brain, immune functions, hormones and energy metabolism.

Kidney function was monitored using change in eGFR over time. Despite its limited accuracy, especially in children with poor muscle bulk, it was the only feasible test which could be done at regular intervals at follow-up visits. The results of eGFR at the time of presentation and at last follow up for the two race groups are depicted in table 3.

eGFR= Estimated glomerular filtration rate

\*One black child with CKD stage 5 who had a successful kidney transplant is included in the number of black children with stage 4 and 5 CKD.

Table 3. eGFR at the Time of Presentation and During Follow Up in the Two Race Groups

Significantly more black compared to white children had stage 4 or 5 CKD on presentation, 7.1% vs. 1.3% respectively (p=0.03), or had developed stage 4 or 5 CKD at the time of last follow up, 19.0% vs. 3.8% respectively (p= 0.000).

serum C3 have been quoted as suggestive of MCNS with an expected good prognosis (International Study of Kidney Disease in Children 1978:159). In this study 67% of the children with MCNS fulfilled the criteria for the diagnosis, apart from not having a normal blood pressure. This finding has been described by others (Habib et al 1971) which

Hypertension was present in 227/358 (63.4%) children at presentation of whom 171/227 (47.8%) required treatment with antihypertensive drugs for at least 6 weeks. Diuretics were used for symptomatic management of oedema and were often used as a first line antihypertensive drug in children considered to have volume overload. Of those with persistent hypertension 146/171 (85.4%) received an ACE-inhibitor as the preferred antihypertensive drug. Overall 213/358 (59.5%) received an ACE-inhibitor for its antiproteinuric effect. Renal function and s-potassium were monitored in all children who were treated with an ACE-inhibitor. No child experienced an allergic response or developed significant coughing with this treatment. An acute increase in s-creatinine levels occurred in some patients, usually in association with volume contraction, which was reversible in all

The mean s-albumin level at the time of presentation was 13.2 5.2 g/L. Some patients had below detectable s-albumin levels and for these the lowest value documented was an arbitrary level of 10g/L for the purpose of statistical analysis. This means that the true mean level was in fact lower. The mean s-cholesterol at the time of presentation was 11.4 7.3 mmol/L. As already stated above, statins were only prescribed to a limited number of older children with persistent hypercholesterolaemia. The main reason why younger children with similar high cholesterol levels were not treated with statins is the lack of long-term safety information on the effects of these drugs on the developing brain, immune functions,

Kidney function was monitored using change in eGFR over time. Despite its limited accuracy, especially in children with poor muscle bulk, it was the only feasible test which could be done at regular intervals at follow-up visits. The results of eGFR at the time of

> **White children n=80**

**eGFR last follow up n = 358**

> **White children n=80**

**Black children n=278**

presentation and at last follow up for the two race groups are depicted in table 3.

**eGFR at presentation n = 358**

**1 ≥90** 189 (68.0%) 55 (68.8%) 178 (64.0%) 66 (82.5%) **2 60-89** 42 (15.1%) 20 (25.0%) 29 (10.4%) 10 (12.5) **3 30-59** 27 (9.7%) 4 (5.0%) 18(6.5%) 1 (1.3%) **4 + 5 <29** 20 (7.1%) 1(1.3%) 53(19.0%)\* 3 (3.8%)

\*One black child with CKD stage 5 who had a successful kidney transplant is included in the number of

Table 3. eGFR at the Time of Presentation and During Follow Up in the Two Race Groups Significantly more black compared to white children had stage 4 or 5 CKD on presentation, 7.1% vs. 1.3% respectively (p=0.03), or had developed stage 4 or 5 CKD at the time of last

**n=278**

questions the validity of the criteria for diagnosing MCNS.

cases with fluid resuscitation.

hormones and energy metabolism.

**CKD Stage**  **eGFR1**

**(ml/min/1.73m2)**

 **Black children**

eGFR= Estimated glomerular filtration rate

follow up, 19.0% vs. 3.8% respectively (p= 0.000).

black children with stage 4 and 5 CKD.

A secondary cause for NS was identified in 26 (7.2%) children including Henoch-Schőnlein purpura, systemic lupus erythematosus, chronic hepatitis B infection, HIV infection and IgA glomerulonephritis. Ten children (2.8%) had chronic hepatitis B associated nephropathy. None of them were given any immunosuppressive treatment, interferon or other specific antiviral treatment. In eleven children a genetic cause of NS was suspected.

CNS was diagnosed in 25/358 (7%) children, none of whom had a syndromic form of CNS. Investigations for mutations of *NPHS1, NPHS2* and *WT1* were not done in any of the children with CNS or suspected familial NS because of unavailability.

Kidney biopsies were performed in 318/358 (89%) children. The main histological diagnoses are depicted in table IV. Eighteen children had inconclusive histology which was reported as "FSGS cannot be excluded." In these cases there was a chronic inflammatory cell infiltrate in the interstitium, interstitial fibrosis and tubulo-interstitial atrophy suggestive of FSGS but the biopsy sample did not have glomeruli with focal sclerosis. If this group of children is added to the group with definite FSGS, the frequency of FSGS increases to 98/318 (31%). Eleven children (10 black, 1 white) were diagnosed with immune complex glomerulonephritis (ICGN), based on the presence of immune deposits in the basement membrane on electron microscopy examination and another 26 (25 black, 1 white) had ICGN with secondary glomerular sclerosis.

\*Statistically significant

\*\*MCNS-FSGS: Histology was reported as "FSGS cannot be excluded" and was therefore inconclusive but very suggestive of FSGS due to the presence of a chronic inflammatory cell infiltrate in the interstitium, interstitial fibrosis and tubular atrophy on the biopsy.

\*\*\*Includes all children who had kidney biopsies, including the children with congenital nephrotic syndrome.

Table 4. Main Histological Subtypes of Nephrotic Syndrome (n = 318)

In table 5. the frequencies of all the histological subtypes excluding CNS are depicted, which is in line with the procedure followed by the ISKDC. CNS is considered a distinct form of NS with a unique etio-pathogenesis and a high frequency of underlying genetic mutations

Nephrotic Syndrome in Children – Studies from South Africa 447

treated with cyclophosphamide, 46 were white and 54 black. The response rate to this treatment was statistically significantly different in the white and black children. Sustained remission was achieved in 37/46 (80%) white and in 23/54 (43%) black children (P=0.002; 95% CI 2.2 – 13.7). The ISKDC reported no benefit of orally administered cyclophosphamide and prednisone compared to prednisone alone for the treatment of steroid resistant NS (Tarshish, P et al. 1996: 590). Their report and the poor response of children with steroid resistant NS in this study prompted discontinuation of cyclophosphamide treatment in children with steroid resistant NS since 2007. No patient experienced side effects of cyclophosphamide treatment, but they were all monitored at least every 10 to 14 days throughout the duration of the treatment. Several children who had been in contact with chicken pox were given human varicella-zoster immune globulin and/or acyclovir

Acute reversible renal failure occurred in 35/358 (9.8%) children and thrombotic complications, other than strokes in 9/358 (2.5%). Six children (1.7%) developed strokes, one of whom developed bilateral sequential middle cerebral artery thromboses a few months apart. She was one of a family of 3 children who all had steroid resistant NS. At the time that she developed the first stroke she was not dehydrated, but had a mild lower respiratory tract infection, iron deficiency anaemia and a thrombocytosis, which are known risk factors

Fourty eight percent of all children experienced acute invasive bacterial infections, including pneumonia, peritonitis and septicaemia. In those with steroid sensitive NS acute bacterial infections occurred during relapses. The frequency of infection was inversely related to age and was particularly high in children younger than 3 months. Of these children 87% developed serious infections compared to 39% of children older than 6 years. Streptococcus pneumoniae was the predominant causal organism, followed by Escherichia coli and other gram negative organisms. Twenty six children (7.3%) developed peritonitis of whom three demised due to pneumococcal septicaemic shock.  Until recently pneumococcal polysaccharide vaccine was given to all children younger than 5 years at the time of their first presentation, despite its limited efficacy in children younger than 2 years. Since 2009 the pneumococcal conjugate vaccine is available in South Africa which is used for revaccination

Chronic hepatitis B infection (positive HBsAg and/or HBeAg) occurred in 10/358 (2.8%) children, all of whom were black. Hepatitis B vaccine was included in the routine immunization schedule of children in South Africa since 1991 and since that time no child was diagnosed with hepatitis B related NS. No child had hepatitis C related NS. Investigations to rule out CMV infection were only done in children with CNS and in those with atypical clinical features of NS, including anaemia, hepatosplenomegaly, skin rash or positive central nervous system signs. In most cases only CMV IgM and IgG were done, which were often both positive due to unexplained reasons at the time, because the test for CMV viral load was not available. Should a CMV infection be diagnosed it is not necessarily

All children were screened for underlying Mycobacerium tuberculosis infection with a chest X-ray, gastric aspirates or induced sputum cultures and Mantoux test (skin prick test with intradermal injection of purified protein derivative of Mycobacterium tuberculosis). Because

prophylactically, but none developed serious chicken pox.

for thrombo-embolic complications in children with nephrotic syndrome.

of this group of children. Long term prophylactic penicillin was not used.

**7.2 Morbidity and mortality**

proof of the causality of the NS.

and is therefore usually not analysed with other forms of INS. Kidney biopsies were done in 318 children (64 white and 254 black). After exclusion of the 25 children with CNS, all of whom were black, the frequencies of the histopathological subtypes of only the remaining 229 black children changed.

**\***Statistically significant

\*\*MCNS-FSGS: Histology was reported as "FSGS cannot be excluded" and was therefore inconclusive but very suggestive of FSGS due to the presence of chronic inflammatory cell infiltrate in the interstitium, interstitial fibrosis and tubular atrophy on the biopsy.

\*\*\*All children who had kidney biopsies, but excluding the children with congenital nephrotic syndrome.

Table 5. Histological Subtypes of Nephrotic Syndrome Excluding Children with Congenital Nephrotic Syndrome (n=293)

The incidences of the four major histological subtypes (MCNS, FSGS, membranous nephropathy, mesangiocapillary glomerulonephritis were significantly higher in the black children (Table 5).

### **7.1 Results of treatment**

Remission with oral corticosteroid treatment was achieved in 33/41(81%) white vs 33/59(56%) black children (p=0.02) who had MCNS. The response rate of the black children is similar to the 60% response rate in black children reported previously from Kalafong Hospital (Prinsloo JG. 1986:375) but lower than the 78% response rate reported a decade later in children from the Chris-Hani Baragwanath Hospital (Johannesburg), both tertiary hospitals in South Africa (Thomson 1997:402). Oral corticosteroid treatment resulted in remission in 3/9 white children and 8/40 black children with FSGS (p=0.6). In the combined group of children with FSGS and MCNS-FSGS 9/13 (69.2%) white children vs 4/14 (28.5%) (p<0.05) black children went into remission with this treatment. Twenty five children who failed to respond to oral corticosteroid treatment were treated with a course of intravenous methylprednisolone of whom only 4 (one white and 3 black children) went into complete remission. This form of treatment was abandoned because of its poor efficacy, high toxicity and cost and the disruptive effect it had on school attendance. Hundred children were treated with cyclophosphamide, 46 were white and 54 black. The response rate to this treatment was statistically significantly different in the white and black children. Sustained remission was achieved in 37/46 (80%) white and in 23/54 (43%) black children (P=0.002; 95% CI 2.2 – 13.7). The ISKDC reported no benefit of orally administered cyclophosphamide and prednisone compared to prednisone alone for the treatment of steroid resistant NS (Tarshish, P et al. 1996: 590). Their report and the poor response of children with steroid resistant NS in this study prompted discontinuation of cyclophosphamide treatment in children with steroid resistant NS since 2007. No patient experienced side effects of cyclophosphamide treatment, but they were all monitored at least every 10 to 14 days throughout the duration of the treatment. Several children who had been in contact with chicken pox were given human varicella-zoster immune globulin and/or acyclovir prophylactically, but none developed serious chicken pox.

#### **7.2 Morbidity and mortality**

446 An Update on Glomerulopathies – Clinical and Treatment Aspects

and is therefore usually not analysed with other forms of INS. Kidney biopsies were done in 318 children (64 white and 254 black). After exclusion of the 25 children with CNS, all of whom were black, the frequencies of the histopathological subtypes of only the remaining

 MCNS 42(65.6) 67(29.3) 109 (37.2) <0.000\* Focal segmental glomerulosclerosis (FSGS) 9 (14.0) 71(31.0) 80 (27.3) 0.004\* MCNS – FSGS \*\* 7(10.9) 11 (4.8) 18 (6.1) 0.07 Immune complex glomerulonephritis (ICGN) 1(1.6) 10 (4.4) 11(3.7) 0.26 ICGN and secondary FSGS 1 (1.6) 25( 11.0) 26 (8.9) 0.01\* Membranous nephropathy 0 (0) 14 (6.1) 14 (4.8) 0.03\* Mesangiocapillary glomerulonephritis 1 (1.6) 12 (5.2) 13 (4.4) 0.18

\*\*MCNS-FSGS: Histology was reported as "FSGS cannot be excluded" and was therefore inconclusive

Table 5. Histological Subtypes of Nephrotic Syndrome Excluding Children with Congenital

The incidences of the four major histological subtypes (MCNS, FSGS, membranous nephropathy, mesangiocapillary glomerulonephritis were significantly higher in the black

Remission with oral corticosteroid treatment was achieved in 33/41(81%) white vs 33/59(56%) black children (p=0.02) who had MCNS. The response rate of the black children is similar to the 60% response rate in black children reported previously from Kalafong Hospital (Prinsloo JG. 1986:375) but lower than the 78% response rate reported a decade later in children from the Chris-Hani Baragwanath Hospital (Johannesburg), both tertiary hospitals in South Africa (Thomson 1997:402). Oral corticosteroid treatment resulted in remission in 3/9 white children and 8/40 black children with FSGS (p=0.6). In the combined group of children with FSGS and MCNS-FSGS 9/13 (69.2%) white children vs 4/14 (28.5%) (p<0.05) black children went into remission with this treatment. Twenty five children who failed to respond to oral corticosteroid treatment were treated with a course of intravenous methylprednisolone of whom only 4 (one white and 3 black children) went into complete remission. This form of treatment was abandoned because of its poor efficacy, high toxicity and cost and the disruptive effect it had on school attendance. Hundred children were

Other 3 (4.7) 19 (8.3) 22 (7.5)

\*\*\*Total 64 (100) 229 (100) 293 (100)

but very suggestive of FSGS due to the presence of chronic inflammatory cell infiltrate in the

\*\*\*All children who had kidney biopsies, but excluding the children with congenital nephrotic

interstitium, interstitial fibrosis and tubular atrophy on the biopsy.

**\***Statistically significant

children (Table 5).

**7.1 Results of treatment**

Nephrotic Syndrome (n=293)

syndrome.

**Histological diagnosis White**

Acute reversible renal failure occurred in 35/358 (9.8%) children and thrombotic complications, other than strokes in 9/358 (2.5%). Six children (1.7%) developed strokes, one of whom developed bilateral sequential middle cerebral artery thromboses a few months apart. She was one of a family of 3 children who all had steroid resistant NS. At the time that she developed the first stroke she was not dehydrated, but had a mild lower respiratory tract infection, iron deficiency anaemia and a thrombocytosis, which are known risk factors for thrombo-embolic complications in children with nephrotic syndrome.

Fourty eight percent of all children experienced acute invasive bacterial infections, including pneumonia, peritonitis and septicaemia. In those with steroid sensitive NS acute bacterial infections occurred during relapses. The frequency of infection was inversely related to age and was particularly high in children younger than 3 months. Of these children 87% developed serious infections compared to 39% of children older than 6 years. Streptococcus pneumoniae was the predominant causal organism, followed by Escherichia coli and other gram negative organisms. Twenty six children (7.3%) developed peritonitis of whom three demised due to pneumococcal septicaemic shock.  Until recently pneumococcal polysaccharide vaccine was given to all children younger than 5 years at the time of their first presentation, despite its limited efficacy in children younger than 2 years. Since 2009 the pneumococcal conjugate vaccine is available in South Africa which is used for revaccination of this group of children. Long term prophylactic penicillin was not used.

Chronic hepatitis B infection (positive HBsAg and/or HBeAg) occurred in 10/358 (2.8%) children, all of whom were black. Hepatitis B vaccine was included in the routine immunization schedule of children in South Africa since 1991 and since that time no child was diagnosed with hepatitis B related NS. No child had hepatitis C related NS. Investigations to rule out CMV infection were only done in children with CNS and in those with atypical clinical features of NS, including anaemia, hepatosplenomegaly, skin rash or positive central nervous system signs. In most cases only CMV IgM and IgG were done, which were often both positive due to unexplained reasons at the time, because the test for CMV viral load was not available. Should a CMV infection be diagnosed it is not necessarily proof of the causality of the NS.

All children were screened for underlying Mycobacerium tuberculosis infection with a chest X-ray, gastric aspirates or induced sputum cultures and Mantoux test (skin prick test with intradermal injection of purified protein derivative of Mycobacterium tuberculosis). Because

Nephrotic Syndrome in Children – Studies from South Africa 449

Kaplan-Meier Renal Survival Estimates

0 50 100 150 200 Time to renal failure(Months)

Kaplan-Meier Patient Survival Estimates

0 50 100 150 200 Time to patient death(Months)

Black children White children

Black children White children

0.00

> 0.00

> 0.25

> 0.50

Survival proportion

0.75

1.00

Fig. 1. Kaplan-Meier estimation of renal survival

Fig. 2. Kaplan-Meier estimation of patient survival

0.25

0.50

Survival proportion

0.75

1.00

children uncommonly have sputum positive tuberculosis, several of our patients received empiric anti-tuberculous treatment for 6 months when the diagnosis could not be unequivocally excluded. A high prevalence of tuberculosis associated with a deleterious effect on renal function was reported in black children with FSGS. (Kala et al.1993:392). It has been postulated that immune responses mediated by infections with Mycobacterium tuberculosis and HI-virus may contribute to glomerulosclerosis. Mycobacterium tuberculosis infection was present in too few patients in this study to draw any conclusion. Investigations for HIV infection were only done in children who had clinical features suggestive of the disease and whose parents had given consent to testing. It is therefore not possible to report on the true incidence of NS associated with HIV infection. Patients with HIV infection had a variety of histological lesions, including, immune complex glomerulonephritis, immunotactoid and fibrillary glomerulonephritis and FSGS. No patient had HIV collapsing glomerulopathy which has been reported as one of the commonest histological lesions in black adult patients with HIV infection. Recently HIV- associated kidney disease has been reported to have become the most common form of kidney disease in children seen in the renal unit at

one of the academic hospitals in South Africa. (Bhimma R, 2009:15) Only one infant with CNS had congenital syphilis and treatment with penicillin did not result in cure of the disease. Chronic "quartan malarial nephropathy" or other parasitic related forms of NS did not occur.

#### **7.3 Outcome**

At presentation 21/358 children had CKD stage 4 or 5. Of the black children 20/278 (7.2%) had CKD stage 4 or 5 compared to 1/80(1.3%) white children (p=0.03). Over the period of follow up more black children (53/278) (19%) developed stage 4 or 5 CKD compared to white children (3/80)(3.8%)(p= 0.000). Kaplan-Meier estimation of renal survival depicting the difference in renal survival in black and white children is demonstrated in Fig1.  Persistent nephrotic range proteinuria is associated with a rapid progression to end-stage kidney disease. Several children in this study had long standing suboptimal management of nephrotic range proteinuria when presenting to the SBAH which contributed to a more rapid progression to end stage kidney disease.

Forty three patients died during the follow up period. Three (3.7%) white children died of whom 2 succumbed to complications of renal failure (renal deaths) and one died due to pneumococcal septicaemia (non renal death). Forty black children died during the follow up period, mostly due to end stage renal failure. In the black children infectious related deaths occurred mostly in the children with congenital NS. Black children had a significantly higher mortality compared to white children (40/268 vs. 3/80) (p<0.001). Kaplan-Meier patient survival estimate depicting the difference in patient survival for black and white childrenis demonstrated in Fig 2.

### **8. Discussion**

This study population differs in several aspects from those reported from developed countries. The majority of patients are black with an inherent risk of CKD due to a genetic predisposition aggravated by poor socio-economic circumstances and chronic infections. Poor prognostic indicators namely stunting, profound hypoalbuminaemia, long standing nephrotic-range proteinuria, hypertension and impaired kidney function are common at presentation against a background of tuberculosis and HIV infection.

children uncommonly have sputum positive tuberculosis, several of our patients received empiric anti-tuberculous treatment for 6 months when the diagnosis could not be unequivocally excluded. A high prevalence of tuberculosis associated with a deleterious effect on renal function was reported in black children with FSGS. (Kala et al.1993:392). It has been postulated that immune responses mediated by infections with Mycobacterium tuberculosis and HI-virus may contribute to glomerulosclerosis. Mycobacterium tuberculosis infection was present in too few patients in this study to draw any conclusion. Investigations for HIV infection were only done in children who had clinical features suggestive of the disease and whose parents had given consent to testing. It is therefore not possible to report on the true incidence of NS associated with HIV infection. Patients with HIV infection had a variety of histological lesions, including, immune complex glomerulonephritis, immunotactoid and fibrillary glomerulonephritis and FSGS. No patient had HIV collapsing glomerulopathy which has been reported as one of the commonest histological lesions in black adult patients with HIV infection. Recently HIV- associated kidney disease has been reported to have become the most common form of kidney disease in children seen in the renal unit at

Only one infant with CNS had congenital syphilis and treatment with penicillin did not result in cure of the disease. Chronic "quartan malarial nephropathy" or other parasitic

At presentation 21/358 children had CKD stage 4 or 5. Of the black children 20/278 (7.2%) had CKD stage 4 or 5 compared to 1/80(1.3%) white children (p=0.03). Over the period of follow up more black children (53/278) (19%) developed stage 4 or 5 CKD compared to white children (3/80)(3.8%)(p= 0.000). Kaplan-Meier estimation of renal survival depicting the difference in renal survival in black and white children is demonstrated in Fig1.  Persistent nephrotic range proteinuria is associated with a rapid progression to end-stage kidney disease. Several children in this study had long standing suboptimal management of nephrotic range proteinuria when presenting to the SBAH

Forty three patients died during the follow up period. Three (3.7%) white children died of whom 2 succumbed to complications of renal failure (renal deaths) and one died due to pneumococcal septicaemia (non renal death). Forty black children died during the follow up period, mostly due to end stage renal failure. In the black children infectious related deaths occurred mostly in the children with congenital NS. Black children had a significantly higher mortality compared to white children (40/268 vs. 3/80) (p<0.001). Kaplan-Meier patient survival estimate depicting the difference in patient survival for black and white

This study population differs in several aspects from those reported from developed countries. The majority of patients are black with an inherent risk of CKD due to a genetic predisposition aggravated by poor socio-economic circumstances and chronic infections. Poor prognostic indicators namely stunting, profound hypoalbuminaemia, long standing nephrotic-range proteinuria, hypertension and impaired kidney function are common at

one of the academic hospitals in South Africa. (Bhimma R, 2009:15)

which contributed to a more rapid progression to end stage kidney disease.

presentation against a background of tuberculosis and HIV infection.

related forms of NS did not occur.

childrenis demonstrated in Fig 2.

**8. Discussion**

**7.3 Outcome**

Fig. 1. Kaplan-Meier estimation of renal survival

Fig. 2. Kaplan-Meier estimation of patient survival

Nephrotic Syndrome in Children – Studies from South Africa 451

septicaemia. Management of the children with CNS was particularly challenging, due to their serious immune compromised state and high frequency of recurring infections. All children with CNS were black and screening for a possible infectious cause was not very fruitful. Genetic studies were not undertaken in any of our patients as we do not have access to genetic laboratory services. Kidney biopsy revealed idiopathic FSGS or secondary glomerular sclerosis in 15/25 children with CNS. A very dense chronic inflammatory cell infiltrate was present in all cases. Children with CNS were not treated with corticosteroids or other immunosuppressive drugs. Most of them remained in hospital for long periods or required frequent admissions for treatment of bacterial infections or gastroenteritis. An ACE inhibitor was not prescribed to any child less than 3 months old and was usually only given

Because of the lower incidence of MCNS in black children in South Africa first reported in 1979, (Bhimma et al. 1997:429; Lewin, et al. 1979: 88) it has been our practice to biopsy all black children at the time of their first presentation. For the same reason paediatric nephrologists elsewhere in Africa have also advocated pre-treatment renal biopsies in their patients. Olowu et al. (Olowu et al. 2010:200] reported that only 18.5% of the black children

Most centres in developed countries are still following the ISKDC recommendation regarding biopsies despite worldwide reports of an increasing incidence of FSGS in both children and adults. Filler et al (Filler et al. 2003 :1107) reported a declining incidence of MCNS from 81.1% to 64% and an increasing incidence of FSGS from 10.8 to 24.7% of FSGS in their childhood population in Ontario, over two time periods 1985-1993 and 1993-2002. The incidence of MCNS in the first period did not differ significantly from that reported by the ISKDC (International Study of Kidney Disease in Children 1978: 13) and although not specifically reported, the inference is made that the majority of their patients responded to corticosteroid therapy. The incidence of FSGS in their patients has more than doubled over 17 years while the population under study remained stable. Race is not mentioned in their study. Despite an alarming increase in the incidence of FSGS in their patients, they argue that empirical steroid treatment with a cut-off point at 28 days is still justifiable. During the second period of their study the incidence of MCNS is similar to the incidence of MCNS in white children in our study, 64.7% vs. 65.6 % and the incidence of FSGS slightly less than that of FSGS in black patients in our study 24.7%

Already in 1997 Thomson et al. (Thomson, P.D. 1997:508), performing pre-treatment biopsies in all their black patients, reported an incidence of FSGS in 31.3% which is identical to the 31% incidence of FSGS in black patients in this study. It appears that there has not been an increase in the incidence of FSGS in black children in Gauteng Province in South

It can be expected that the HIV epidemic has contributed to the incidence of CKD in South Africa in general, but its possible role in the development of FSGS, or its contribution to an increase in the incidence of FSGS, is uncertain. Local multi-centre prospective research studies in patients with HIV-associated nephropathy will be necessary to explore this

Primary FSGS is a spectrum of podocytopathies caused by a variety of contributing etiologies, including genetics, infections, environment, including the intra-uterine environment, drugs and toxins. It is an aggressive disease, more so in black children compared to white children. The rationale of performing a kidney biopsy at presentation is

to children older than 12 months.

vs. 31%.

question.

Africa over this period.

with INS in their study of Nigerian patients had MCNS.

The results of this audit confirm that significant racial differences exist in the clinical presentation, histological subtypes, response to treatment and outcome in South African children with NS. Similar findings have been reported by other study groups in South Africa (Bhimma et al. 2006: 1847; Bhimma R, 1997: 429), from other countries in Africa (Yao Doe, J. et al. 2006: 672; Olowu et al. 2010:200) and also from elsewhere in the world (Ingulli, E. & Tejani, A. 2001:393). In their study on idiopathic FSGS in children Ingulli et al. (Ingulli, E. & Tejani, A. 2001:393) reported that the rate of FSGS was higher (32.2% vs. 20%), and progress to end stage kidney disease was more common (78% vs. 33%) in black and Hispanic compared to white children. Olowu et al. (Olowu et al. 2010:200) reported an incidence of 18.5 % MCNS and 25.9% FSGS in their study of black Nigerian children with INS. Ethnic differences in the incidences of FSGS have now been well established. Over the past 10 years there have been several reports of an increasing incidence of FSGS in children (Borges et al. 2007:1309; Filler et al. 2003: 1107)

In this study 77% of the children were black and 23% were white. There was a significant difference in the incidences of the main histological subtypes (MCNS, FSGS, immune complex glomerulonephritis, secondary FSGS and membranous nephropathy) between black and white children. The incidence of MCNS was 65.6% and 29.3% (p<0.000) and of FSGS, 14% and 31% (p=0.004) in white and black children respectively.

The first course of corticosteroid treatment was often longer or more intense than that recommended by the ISKDC (International Study of Kidney Disease in Children: 1978:13) because of delayed achievement of remission or only partial response after the first four weeks. Corticosteroid treatment was also often given daily rather than on alternate days because parents failed to understand alternate day dosing schemes. White children with MCNS had a better response to oral corticosteroid treatment compared to black children with MCNS (80% vs 56%; p=0.02). Remission with oral corticosteroid treatment was achieved in more white children with FSGS compared to black children with FSGS, although this difference did not reach statistical significance (33% vs 20 %; p=0.6). Response rates in both race groups in this study were much lower compared to the 93.1% response rate reported by the ISKDC (International Study of Kidney Disease in Children: 1978:13).

After 2000 we stopped using high dose intravenous methylprednisolone for the treatment of steroid resistant NS in our patients for several reasons. It is too costly, it places a heavy burden on the family and child, and only 4 of 25 children (16%) went into remission with this treatment. This very poor response rate compared to that of Mendoza et al (Mendoza, S.A. et al. 1990:303), who reported complete remission in 52% of their patients, can possibly be explained by the fact that we omitted an alkylating agent in our treatment regimen. Adhikari et al (Adhikari et al. 1997:423) reported a dismal outcome in 12 South African children with FSGS who were treated with a combination of intravenous methylprednisolone and an alkylating agent. Although they considered this treatment as "promising," their patients developed serious side effects including alopecia, cataracts, leukopaenia, systemic candidiasis, gram negative septicaemia, and one child demised of a serious infection which was undoubtedly caused by the severe immune suppression associated with the treatment.

Infections remain a serious risk to all children during a relapse of NS, which is practically always for those with steroid resistant NS. This risk is intensified in those living in poor socio-economic circumstances. Forty eight percent of our patients experienced acute invasive bacterial infections and three succumbed to documented pneumococcal

The results of this audit confirm that significant racial differences exist in the clinical presentation, histological subtypes, response to treatment and outcome in South African children with NS. Similar findings have been reported by other study groups in South Africa (Bhimma et al. 2006: 1847; Bhimma R, 1997: 429), from other countries in Africa (Yao Doe, J. et al. 2006: 672; Olowu et al. 2010:200) and also from elsewhere in the world (Ingulli, E. & Tejani, A. 2001:393). In their study on idiopathic FSGS in children Ingulli et al. (Ingulli, E. & Tejani, A. 2001:393) reported that the rate of FSGS was higher (32.2% vs. 20%), and progress to end stage kidney disease was more common (78% vs. 33%) in black and Hispanic compared to white children. Olowu et al. (Olowu et al. 2010:200) reported an incidence of 18.5 % MCNS and 25.9% FSGS in their study of black Nigerian children with INS. Ethnic differences in the incidences of FSGS have now been well established. Over the past 10 years there have been several reports of an increasing incidence of FSGS in children

In this study 77% of the children were black and 23% were white. There was a significant difference in the incidences of the main histological subtypes (MCNS, FSGS, immune complex glomerulonephritis, secondary FSGS and membranous nephropathy) between black and white children. The incidence of MCNS was 65.6% and 29.3% (p<0.000) and of

The first course of corticosteroid treatment was often longer or more intense than that recommended by the ISKDC (International Study of Kidney Disease in Children: 1978:13) because of delayed achievement of remission or only partial response after the first four weeks. Corticosteroid treatment was also often given daily rather than on alternate days because parents failed to understand alternate day dosing schemes. White children with MCNS had a better response to oral corticosteroid treatment compared to black children with MCNS (80% vs 56%; p=0.02). Remission with oral corticosteroid treatment was achieved in more white children with FSGS compared to black children with FSGS, although this difference did not reach statistical significance (33% vs 20 %; p=0.6). Response rates in both race groups in this study were much lower compared to the 93.1% response rate reported by the ISKDC (International Study of Kidney Disease in Children: 1978:13). After 2000 we stopped using high dose intravenous methylprednisolone for the treatment of steroid resistant NS in our patients for several reasons. It is too costly, it places a heavy burden on the family and child, and only 4 of 25 children (16%) went into remission with this treatment. This very poor response rate compared to that of Mendoza et al (Mendoza, S.A. et al. 1990:303), who reported complete remission in 52% of their patients, can possibly be explained by the fact that we omitted an alkylating agent in our treatment regimen. Adhikari et al (Adhikari et al. 1997:423) reported a dismal outcome in 12 South African children with FSGS who were treated with a combination of intravenous methylprednisolone and an alkylating agent. Although they considered this treatment as "promising," their patients developed serious side effects including alopecia, cataracts, leukopaenia, systemic candidiasis, gram negative septicaemia, and one child demised of a serious infection which was undoubtedly caused by the severe immune suppression

Infections remain a serious risk to all children during a relapse of NS, which is practically always for those with steroid resistant NS. This risk is intensified in those living in poor socio-economic circumstances. Forty eight percent of our patients experienced acute invasive bacterial infections and three succumbed to documented pneumococcal

FSGS, 14% and 31% (p=0.004) in white and black children respectively.

(Borges et al. 2007:1309; Filler et al. 2003: 1107)

associated with the treatment.

septicaemia. Management of the children with CNS was particularly challenging, due to their serious immune compromised state and high frequency of recurring infections. All children with CNS were black and screening for a possible infectious cause was not very fruitful. Genetic studies were not undertaken in any of our patients as we do not have access to genetic laboratory services. Kidney biopsy revealed idiopathic FSGS or secondary glomerular sclerosis in 15/25 children with CNS. A very dense chronic inflammatory cell infiltrate was present in all cases. Children with CNS were not treated with corticosteroids or other immunosuppressive drugs. Most of them remained in hospital for long periods or required frequent admissions for treatment of bacterial infections or gastroenteritis. An ACE inhibitor was not prescribed to any child less than 3 months old and was usually only given to children older than 12 months.

Because of the lower incidence of MCNS in black children in South Africa first reported in 1979, (Bhimma et al. 1997:429; Lewin, et al. 1979: 88) it has been our practice to biopsy all black children at the time of their first presentation. For the same reason paediatric nephrologists elsewhere in Africa have also advocated pre-treatment renal biopsies in their patients. Olowu et al. (Olowu et al. 2010:200] reported that only 18.5% of the black children with INS in their study of Nigerian patients had MCNS.

Most centres in developed countries are still following the ISKDC recommendation regarding biopsies despite worldwide reports of an increasing incidence of FSGS in both children and adults. Filler et al (Filler et al. 2003 :1107) reported a declining incidence of MCNS from 81.1% to 64% and an increasing incidence of FSGS from 10.8 to 24.7% of FSGS in their childhood population in Ontario, over two time periods 1985-1993 and 1993-2002. The incidence of MCNS in the first period did not differ significantly from that reported by the ISKDC (International Study of Kidney Disease in Children 1978: 13) and although not specifically reported, the inference is made that the majority of their patients responded to corticosteroid therapy. The incidence of FSGS in their patients has more than doubled over 17 years while the population under study remained stable. Race is not mentioned in their study. Despite an alarming increase in the incidence of FSGS in their patients, they argue that empirical steroid treatment with a cut-off point at 28 days is still justifiable. During the second period of their study the incidence of MCNS is similar to the incidence of MCNS in white children in our study, 64.7% vs. 65.6 % and the incidence of FSGS slightly less than that of FSGS in black patients in our study 24.7% vs. 31%.

Already in 1997 Thomson et al. (Thomson, P.D. 1997:508), performing pre-treatment biopsies in all their black patients, reported an incidence of FSGS in 31.3% which is identical to the 31% incidence of FSGS in black patients in this study. It appears that there has not been an increase in the incidence of FSGS in black children in Gauteng Province in South Africa over this period.

It can be expected that the HIV epidemic has contributed to the incidence of CKD in South Africa in general, but its possible role in the development of FSGS, or its contribution to an increase in the incidence of FSGS, is uncertain. Local multi-centre prospective research studies in patients with HIV-associated nephropathy will be necessary to explore this question.

Primary FSGS is a spectrum of podocytopathies caused by a variety of contributing etiologies, including genetics, infections, environment, including the intra-uterine environment, drugs and toxins. It is an aggressive disease, more so in black children compared to white children. The rationale of performing a kidney biopsy at presentation is

Nephrotic Syndrome in Children – Studies from South Africa 453

Ingulli, E. & Tejani, A. 2001. Racial differences in the incidence and renal outcome of

International Study of Kidney Disease in Children. 1978. Nephrotic syndrome in children:

Kala, U. et al. 1993. Impact of tuberculosis in children with idiopathic nephrotic syndrome.

K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification,

Lewin, J.R. et al. 1979. The differing histology in black and white children with nephrotic

Manalich, R. et al. 2000. Relationship between weight at birth and the number and size

Mendoza, S.A. et al. 1990. Treatment of steroid-resistant focal segmental

Olowu, W.A. et al. 2010. Reversed Clinical and Morphologic Characteristics of Idiopathic

Prinsloo, J.G. 1986. The nephrotic syndrome in black children at Kalafong Hospital. SAMJ,

Schwartz, G.J. et al. 1987. The use of plasma creatinine concentration for estimating

Srivastava, T. et al. 1991. High incidence of focal segmental glomerulosclerosis in nephrotic

Tarshish, P. et al. 1996. Cyclophoshamide does not benefit patients with focal segmental

Teeninga, N. et al. 2008. Influence of low birth weight on minimal change nephrotic

The Fourth Report of the National High Blood Pressure Education Program Working Group

Thomson, P.D. 1997. Renal problems in black South African children. Pediatr Nephrol, 1,

Valeri, A. et al. 1996. Idiopathic collapsing focal glomerulosclerosis: A clinicopathologic

Vehaskari, V.M. 2007. Developmental origins of adult hypertension: new insights into the

Childhood Nephrotic Syndrome. Int J Nephrol Urol. 2(1), 200 – 211.

syndrome of childhood. *Pediatr Nephrol,* 13, 13-18.

Children. *Pediatr Nephrol,*10:590-593.

study**.** Kidney Int, 50, 1734-1746

role of the kidney. Pediatr Nephrol, 22, 490-495

397.

773.

70:375.

1620.

575.

508-512.

Am, 34, 571-590.

Kidney Int, 13, 159-165.

Dis, 39, S1–S246

*Pediatr Nephrol*, 7, 392-395.

Pediatr Nephrol, 4, 303-307.

syndrome (abstract). *Kidney Int*, 16, 88.

idiopathic focal segmental glomerulosclerosis in children. *Pediatr Nephrol*, 5, 393-

Prediction of histopathology from clinical and laboratory characteristics at the time of diagnosis. A report of the International Study of Kidney Disease in Children.

and stratification. 2002. Kidney Disease Outcome Quality Initiative. Am J Kidney

of renal glomeruli in humans: a histomorphometric study. *Kidney Int, 58,* 770-

glomerulosclerosis with pulse methylprednisolone and alkylating agents.

glomerular filtration rate in infants, children and adolescents. Pediatr Clin North

glomerulosclerosis: Report of the International Study of Kidney Diseases in

syndrome in children, including meta-analysis. *Nephrol Dial Transplant*, 23, 1615-

on High Blood Pressure in Children and Adolescents. 2004. Pediatrics, 114(2), 555-

that it confirms the histological subtype and may give clues to the stage and type of initial injury. It has been suggested that the different variants of FSG may respond differently to treatment (Valeri. et al. 1996: 1734). Immuno-histochemistry and electron microscopy may also help in differentiating primary and secondary forms of FSGS. It is well known that patients with extensive involvement of glomeruli, advanced tubulo-interstitial fibrosis and tubular atrophy are less likely to respond to corticosteroid treatment compared to those with no interstitial involvement. It is questionable whether it is justifiable to expose such a patient who may also happen to be malnourished and have poor social circumstances to aggressive immune suppression for a disease which may not have an immunological background. The possible departure of many of our black patients from a hostile intra uterine environment resulting in low birth weight and low glomerular endowment is an aspect which has not been investigated systematically.

### **9. Conclusions**

Compared to the ISKDC report black children have a lower incidence of MCNS and a higher incidence of FSGS. Black children also have a more aggressive form of FSGS which responds poorly to corticosteroid and other immuno-suppressive treatment.  The results of this study and similar evidence from the rest of Africa suggest that the ISKDC recommendation of empiric corticosteroid treatment in children with INS should not be followed in the management of black children with INS. We suggest that a kidney biopsy should be done at presentation to allow a definitive diagnosis and targeted treatment from the outset.

#### **10. References**

that it confirms the histological subtype and may give clues to the stage and type of initial injury. It has been suggested that the different variants of FSG may respond differently to treatment (Valeri. et al. 1996: 1734). Immuno-histochemistry and electron microscopy may also help in differentiating primary and secondary forms of FSGS. It is well known that patients with extensive involvement of glomeruli, advanced tubulo-interstitial fibrosis and tubular atrophy are less likely to respond to corticosteroid treatment compared to those with no interstitial involvement. It is questionable whether it is justifiable to expose such a patient who may also happen to be malnourished and have poor social circumstances to aggressive immune suppression for a disease which may not have an immunological background. The possible departure of many of our black patients from a hostile intra uterine environment resulting in low birth weight and low glomerular endowment is an aspect which has not

Compared to the ISKDC report black children have a lower incidence of MCNS and a higher incidence of FSGS. Black children also have a more aggressive form of FSGS which responds poorly to corticosteroid and other immuno-suppressive treatment.  The results of this study and similar evidence from the rest of Africa suggest that the ISKDC recommendation of empiric corticosteroid treatment in children with INS should not be followed in the management of black children with INS. We suggest that a kidney biopsy should be done at presentation to allow a

Adhikari, M. et al. 1997. Intensive pulse therapies for focal glomerulosclerosis in South

Bhimma, R. 2009. HIV-associated renal disease in children. The Pediatric Quarterly, 1(4), 15-

Bhimma, R. et al. 2006. Steroid–resistant nephrotic syndrome: the influence of race on

Bhimma, R. et al. 1997. Nephrotic Syndrome in South African Children: changing

Borges, FF. et al. 2007. Is focal segmental glomerulosclerosis increasing in patients with

Filler, G. et al. 2003. Is There Really an Increase in Non Minimal Change Nephrotic

Habib, R. & Kleinknecht, C. 1971. The primary nephrotic syndrome of childhood:

Hodson, E.M. et al. 2006. Intervention for idiopathic steroid-resistant nephrotic syndrome in

Classification and clinicopathologic study of 406 cases. Pathology Annual, 6, 417-

cyclophosphamide sensitivity. *Pediatr Nephrol,* 21, 1847-1853.

perspectives over 20 years. *Pediatr Nephrol*, 11, 429-434.

Syndrome in Children? *Am J Kidney Dis*, 42(6), 1107-1114.

nephrotic syndrome ? *Pediatr Nephrol*, 22, 1309-1313.

children. Cochrane Database Sys Rev, 2, CD003594

been investigated systematically.

definitive diagnosis and targeted treatment from the outset.

African children. *Pediatr Nephrol*, 11:423-428.

**9. Conclusions**

**10. References**

18.

474.

**24**

*Japan*

Toshihiko Ishimitsu

**Blood Pressure Control in**

*Dokkyo Medical University, Mibu, Tochigi,*

**Patients with Glomerulonephritis**

Although the expanding prevalence of lifestyle-related diseases such as diabetes mellitus and hypertension which ultimately cause renal dysfunction, glomerulonephritis still remains as one of the major causes of end-stage renal failure in most countries all over the world. In addition to the immunological therapy using corticosteroids and immunosuppressants, management of non-immunological risk factors such as hypertension, obesity and disorders of glucose and lipid metabolism greatly affect the prognosis of renal function in the treatment of patients with glomerulonephritis. Especially, hypertension is a pivotal risk factor for the progression of renal injuries and the adequate blood pressure control is a matter of primary

In this chapter, the importance of blood pressure control is stressed referring the evidence thus far, and current topics and future prospects are discussed as to the matters such as

Generally, hypertension is diagnosed when the systolic blood pressure is higher than 140mmHg and/or the diastolic blood pressure is higher than 90mmHg. However, this is an arbitrary definition and the linear relation between the blood pressure level and the risk of renal dysfunction can be extended even in the normotensive range in epidemiological studies. Figure 1 shows the relations of blood pressure level categories and the risk of developing end-stage renal failure in 17-year follow-up study of Okinawa prefecture residents in Japan (1). Naturally, hypertension increases the risk of renal failure with elevating grade of blood pressure levels. Moreover, blood pressure levels lower than 140/90mmHg but higher than 130/85mmHg, namely the high-normal blood pressure,

As for the target blood pressure level in the treatment of glomerulonephritis patients, Figure 2 depicts the outcomes of Modification of Diet in Renal Disease (MDRD) study (2) in which the blood pressure control level less than 125/75mmHg brought about slower GFR reduction than the level less than 140/90mmHg in subjects with nondiabetic renal diseases especially when the proteinuria was prominent. Similarly, Figure 3 plots the annual decrease rates of GFR against achieved blood pressure levels in hypertensive subjects with

importance in order to prevent the development of renal dysfunction.

target blood pressure levels and choices of antihypertensive agents.

offers a significant risk for future development of renal failure.

**1. Introduction**

**2. Target blood pressure**

*Department of Hypertension and Cardiorenal Medicine,*

## **Blood Pressure Control in Patients with Glomerulonephritis**

### Toshihiko Ishimitsu

*Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan*

### **1. Introduction**

454 An Update on Glomerulopathies – Clinical and Treatment Aspects

White, R.H.R. et al. 1970. Clinicopathologic study of nephrotic syndrome in childhood.

Yao Doe, J. et al. 2006. Nephrotic syndrome in African children: lack of evidence of "tropical

nephrotic syndrome". Nephrol Dial Transplant, Vol. 21, 672-676.

Lancet, 1,1353-1359.

Although the expanding prevalence of lifestyle-related diseases such as diabetes mellitus and hypertension which ultimately cause renal dysfunction, glomerulonephritis still remains as one of the major causes of end-stage renal failure in most countries all over the world. In addition to the immunological therapy using corticosteroids and immunosuppressants, management of non-immunological risk factors such as hypertension, obesity and disorders of glucose and lipid metabolism greatly affect the prognosis of renal function in the treatment of patients with glomerulonephritis. Especially, hypertension is a pivotal risk factor for the progression of renal injuries and the adequate blood pressure control is a matter of primary importance in order to prevent the development of renal dysfunction.

In this chapter, the importance of blood pressure control is stressed referring the evidence thus far, and current topics and future prospects are discussed as to the matters such as target blood pressure levels and choices of antihypertensive agents.

### **2. Target blood pressure**

Generally, hypertension is diagnosed when the systolic blood pressure is higher than 140mmHg and/or the diastolic blood pressure is higher than 90mmHg. However, this is an arbitrary definition and the linear relation between the blood pressure level and the risk of renal dysfunction can be extended even in the normotensive range in epidemiological studies. Figure 1 shows the relations of blood pressure level categories and the risk of developing end-stage renal failure in 17-year follow-up study of Okinawa prefecture residents in Japan (1). Naturally, hypertension increases the risk of renal failure with elevating grade of blood pressure levels. Moreover, blood pressure levels lower than 140/90mmHg but higher than 130/85mmHg, namely the high-normal blood pressure, offers a significant risk for future development of renal failure.

As for the target blood pressure level in the treatment of glomerulonephritis patients, Figure 2 depicts the outcomes of Modification of Diet in Renal Disease (MDRD) study (2) in which the blood pressure control level less than 125/75mmHg brought about slower GFR reduction than the level less than 140/90mmHg in subjects with nondiabetic renal diseases especially when the proteinuria was prominent. Similarly, Figure 3 plots the annual decrease rates of GFR against achieved blood pressure levels in hypertensive subjects with

Blood Pressure Control in Patients with Glomerulonephritis 457

Thus, it is suggested that the blood pressure should be lowered below the high-normal level in glomerulonephritis patients in order to maximally slow the progression of renal dysfunction. Therefore, the American, European and Japanese guidelines for the management of hypertension recommend the target blood pressure level of less than

Fig. 3. Relationship between the annual decrease in glomerular filtration rate (GFR) and the achieved mean blood pressure level in studies treated hypertensive patients with renal diseases (3). The GFR decline rate was suppressed to the level near to the physiological decrease with aging in patients whose blood pressure was lowered under 130/85mmHg.

According to the hyperfiltration theory proposed by Hostteter and Brenner (7,8), increases in glomerular capillary pressure, referred to as glomerular hypertension, play an important role in the development and the progression of glomerular injuries ultimately resulting in glomerular sclerosis and the loss of its nephron. As indicated in Figure 4, not only high blood pressure but also increased salt intake and decreased urinary sodium excretion resulting in body fluid volume expansion raise intraglomerular capillary pressure and cause glomerular hypertension. In addition, the increases in protein intake and glomerular efferent arteriolar resistance are also the factors that contribute to the elevation of intraglomerular capillary pressure. Long-lasting of sustained glomerular hypertension impairs glomerular capillary endothelium and allows filtration of plasma protein molecules, followed by widening of mesangial area, obstruction of capillary lumen, hyalinosis of glomerular tuft and finally resulting in glomerular sclerosis, abolition of blood flow and filtration function. The loss of glomeruli brings about the atrophy of following renal tubules and nephrons themselves. Once a certain proportion of nephrons fall into atrophy, the intraglomerular capillary pressure and the single nephron filtration glomerular filtration rate of remaining glomeruli increase in order to compensate the reduced renal blood flow and maintain the glomerular filtration rate, which consequently promote further

130/80mmHg in patients with chronic kidney disease (CKD) (4-6).

**3. Glomerular hypertension and hyperfiltration**

development of glomerular hypertension.

renal diseases (3). In patients whose hypertension was not treated, GFR decreased by more than 10mL/min per year. When the blood pressure was lowered to 140/90mmHg, the rate of annual GFR decline was reduced by half. However, considering that the physiological annual GFR decline with aging is about 1mL/min, the annual GFR decline in 140/90mmHg subjects is faster than the natural rate. As compared with this, strict blood pressure lowering to 130/85mmHg or 130/80mmHg yielded retardation of GFR decline to a nearly physiological level in subjects with renal diseases.

Fig. 1. Relationship between the incidence of end-stage renal failure and the blood pressure level (1). The incidence of end-stage renal failure is increased not only in hypertensive subjects but also in subjects with high-normal blood pressure ranging 130-139/85-89 mmHg as compared with lower normal blood pressure subjects.

Fig. 2. The annual decrease in glomerular filtration rate (GFR) in nondiabetic renal disease patients of The Modification of Diet in Renal Disease(MDRD) Study. (2)

renal diseases (3). In patients whose hypertension was not treated, GFR decreased by more than 10mL/min per year. When the blood pressure was lowered to 140/90mmHg, the rate of annual GFR decline was reduced by half. However, considering that the physiological annual GFR decline with aging is about 1mL/min, the annual GFR decline in 140/90mmHg subjects is faster than the natural rate. As compared with this, strict blood pressure lowering to 130/85mmHg or 130/80mmHg yielded retardation of GFR decline to a nearly

Fig. 1. Relationship between the incidence of end-stage renal failure and the blood pressure level (1). The incidence of end-stage renal failure is increased not only in hypertensive

Fig. 2. The annual decrease in glomerular filtration rate (GFR) in nondiabetic renal disease

patients of The Modification of Diet in Renal Disease(MDRD) Study. (2)

subjects but also in subjects with high-normal blood pressure ranging

130-139/85-89 mmHg as compared with lower normal blood pressure subjects.

physiological level in subjects with renal diseases.

Thus, it is suggested that the blood pressure should be lowered below the high-normal level in glomerulonephritis patients in order to maximally slow the progression of renal dysfunction. Therefore, the American, European and Japanese guidelines for the management of hypertension recommend the target blood pressure level of less than 130/80mmHg in patients with chronic kidney disease (CKD) (4-6).

Fig. 3. Relationship between the annual decrease in glomerular filtration rate (GFR) and the achieved mean blood pressure level in studies treated hypertensive patients with renal diseases (3). The GFR decline rate was suppressed to the level near to the physiological decrease with aging in patients whose blood pressure was lowered under 130/85mmHg.

### **3. Glomerular hypertension and hyperfiltration**

According to the hyperfiltration theory proposed by Hostteter and Brenner (7,8), increases in glomerular capillary pressure, referred to as glomerular hypertension, play an important role in the development and the progression of glomerular injuries ultimately resulting in glomerular sclerosis and the loss of its nephron. As indicated in Figure 4, not only high blood pressure but also increased salt intake and decreased urinary sodium excretion resulting in body fluid volume expansion raise intraglomerular capillary pressure and cause glomerular hypertension. In addition, the increases in protein intake and glomerular efferent arteriolar resistance are also the factors that contribute to the elevation of intraglomerular capillary pressure. Long-lasting of sustained glomerular hypertension impairs glomerular capillary endothelium and allows filtration of plasma protein molecules, followed by widening of mesangial area, obstruction of capillary lumen, hyalinosis of glomerular tuft and finally resulting in glomerular sclerosis, abolition of blood flow and filtration function. The loss of glomeruli brings about the atrophy of following renal tubules and nephrons themselves. Once a certain proportion of nephrons fall into atrophy, the intraglomerular capillary pressure and the single nephron filtration glomerular filtration rate of remaining glomeruli increase in order to compensate the reduced renal blood flow and maintain the glomerular filtration rate, which consequently promote further development of glomerular hypertension.

Blood Pressure Control in Patients with Glomerulonephritis 459

epithelial and mesangial cells of glomeruli. In addition, aldosterone, like angiotensin II, constricts the efferent arterioles preferably to the afferent arteriole and increase the intraglomerular capillary pressure and filtration of plasma protein molecules. Thus, aldosterone is also assumed to be a factor exerting detrimental effects to the progression of

Fig. 5. The structure of glomeruli and factors relating to the hemodynamics and hydrauric

Fig. 6. Outlines of the renin-angiotensin-aldosterone system and the biological actions

pressure of glomeruli and glomerular arterioles.

elicited by its components.

glomerular diseases.

Fig. 4. Relations of factors contributing to the increase in intraglomerular capillary pressure and progression of glomerular sclerosis.

In order to stop the progression of this vicious cycle, comprehensive control of factors influencing the intraglomerular capillary pressure elevation such as arterial hypertension and intakes of salt and protein is needed. As mentioned concerning the target blood pressure, strict blood pressure control is important in patients with glomerulonephritis. In controlling the blood pressure, it should be kept in mind that reduction of intraglomerular capillary pressure as well as systemic arterial pressure is essential in order to achieve maximally effective inhibition of glomerular injuries and renal dysfunction. With regard to the hemodynamic aspect of renal microcirculation, intraglomerular capillary pressure is regulated by the balance between vascular resistances of afferent and efferent glomerular arterioles as depicted in Figure 5. A number of neural and humoral factors are known to affect the contraction and dilation of glomerular arterioles. Among them, the reninangiotensin-aldosterone (RAA) system indicated in Figure 6 is assumed to play a pivotal role in the regulation of glomerular hemodynamics. Especially, angiotensin II, a peptide exhibiting prominent bioactivities in the RAA system, induce strong contraction of efferent rather than afferent glomerular arterioles. In addition, angiotensin II facilitates mesangial cell proliferation, increases oxidative stress by activating NAD(P)H oxidase, and induce proinflammatory transcription factor NF-B (9,10). These versatile effects of angiotensin II also contribute to the progression of renal tissue injuries.

On the other hand, angiotensin II stimulates the adrenal cortex to secrete aldosterone, a major mineralocorticoid, which facilitates renal tubular reabsorption of sodium resulting in blood and body fluid volume expansion and blood pressure elevation. Besides this wellknown effect, aldosterone has been shown to promote renal tissue fibrosis and production of extracellular matrices such as collagen (9-11). Moreover, aldosterone injures endothelial,

Fig. 4. Relations of factors contributing to the increase in intraglomerular capillary pressure

In order to stop the progression of this vicious cycle, comprehensive control of factors influencing the intraglomerular capillary pressure elevation such as arterial hypertension and intakes of salt and protein is needed. As mentioned concerning the target blood pressure, strict blood pressure control is important in patients with glomerulonephritis. In controlling the blood pressure, it should be kept in mind that reduction of intraglomerular capillary pressure as well as systemic arterial pressure is essential in order to achieve maximally effective inhibition of glomerular injuries and renal dysfunction. With regard to the hemodynamic aspect of renal microcirculation, intraglomerular capillary pressure is regulated by the balance between vascular resistances of afferent and efferent glomerular arterioles as depicted in Figure 5. A number of neural and humoral factors are known to affect the contraction and dilation of glomerular arterioles. Among them, the reninangiotensin-aldosterone (RAA) system indicated in Figure 6 is assumed to play a pivotal role in the regulation of glomerular hemodynamics. Especially, angiotensin II, a peptide exhibiting prominent bioactivities in the RAA system, induce strong contraction of efferent rather than afferent glomerular arterioles. In addition, angiotensin II facilitates mesangial cell proliferation, increases oxidative stress by activating NAD(P)H oxidase, and induce proinflammatory transcription factor NF-B (9,10). These versatile effects of angiotensin II

On the other hand, angiotensin II stimulates the adrenal cortex to secrete aldosterone, a major mineralocorticoid, which facilitates renal tubular reabsorption of sodium resulting in blood and body fluid volume expansion and blood pressure elevation. Besides this wellknown effect, aldosterone has been shown to promote renal tissue fibrosis and production of extracellular matrices such as collagen (9-11). Moreover, aldosterone injures endothelial,

and progression of glomerular sclerosis.

also contribute to the progression of renal tissue injuries.

epithelial and mesangial cells of glomeruli. In addition, aldosterone, like angiotensin II, constricts the efferent arterioles preferably to the afferent arteriole and increase the intraglomerular capillary pressure and filtration of plasma protein molecules. Thus, aldosterone is also assumed to be a factor exerting detrimental effects to the progression of glomerular diseases.

Fig. 5. The structure of glomeruli and factors relating to the hemodynamics and hydrauric pressure of glomeruli and glomerular arterioles.

Fig. 6. Outlines of the renin-angiotensin-aldosterone system and the biological actions elicited by its components.

Blood Pressure Control in Patients with Glomerulonephritis 461

afferent arterioles and thereby lower intraglomerular capillary pressure effectively (Figure 5). Anderson et al. (19) have shown that an ACE inhibitor lowers intraglomerular capillary pressure, reduces proteinuria and inhibits the progression of glomerular sclerosis more prominently than other antihypertensive drugs in rats with reduced renal mass in which the

In human, it is a distinctive feature that the intraglomerular capillary pressure is elevated and the GFR is increased at the early stage of diabetic nephropathy. This glomerular hypertension facilitates the progression of diabetic nephropathy stages, namely, microalbuminuria, overt proteinuria, a GFR reduction, a serum creatinine increase and end-stage renal failure. Taguma et al. (20) have first reported that an ACE inhibitor reduces proteinuria in patients with diabetic nephropathy, and it is suggested that the suppression of angiotensin II generation brings about alleviation of glomerular hypertension and reduce hydrauric transcapillary filtration pressure of protein. After that, Lewis et al. (21) performed the multi-center collaborative prospective study evaluating the renoprotective effects of an ACE inhibitor in patients with type 1 diabetes mellitus presenting overt proteinuria and demonstrated that captopril inhibited the serum creatinine increase and the incidence of end-stage renal failure. As well as ACE inhibitors, multiple lines of later clinical studies have indicated that ARB are effective in retarding the

With regard to the non-diabetic renal disease such as glomerulonephritis, the ACE Inhibition in Progressive Renal Insufficiency (AIPRI) study (25) and Ramipril Efficacy in Nephropathy (REIN) study (26) showed that ACE inhibitors delay the progression of renal insufficiency in European patients with non-diabetic renal disease. Furthermore, African American Study of Kidney Disease and Hypertension (AASK) (27) suggested that ACE inhibitors slow renal disease progression in African American patients with hypertensive renal disease. Also as for the Asian population, we have reported that an ACE inhibitor and an ARB are effective in reducing proteinuria and slowing the deterioration of renal function in Japanese patients with chronic glomerulonephritis (28,29). Namely, an ACE inhibitor, benazepril, or an ARB, valsartan, inhibited the increase in serum creatinine and reduced proteinuria by 30-40% as compared with placebo (Figure 7,8). In addition, there is another study reported that an ACE inhibitor improved renal outcomes in Chinese patients with advanced stage of non-diabetic

progression of nephropathy at each stage in patients with type 2 diabetes (22-24).

renal disease whose serum creatinine ranged 3.1 to 5.0mg/dL (30).

Fig. 7. Changes in serum creatinine concentrations and urinary protein excretions in

glomerulonephritis patients given the ACE inhibitor or the placebo (28).

circulating RAA system is thought to be suppressed.

Several other hormones and autacoids are known to elicit dilation or contraction of the glomerular arterioles. Atrial natriuretic peptide (ANP), produced by the heart, dilates the afferent arteriole and preserves renal and glomerular blood flow in the state of heart failure (12). This action is supposed to work also in glomerulonephritis patients with reduced renal function because the plasma ANP level is increased by body fluid volume increase and reduced clearance in the kidney. Vascular endothelium produces vasoactive substances such as nitric oxide (NO) and endothelin (ET). NO preferentially dilates and ET preferentially contract the afferent arterioles (13,14). NO is supposed to participate in the mechanism of increased glomerular filtration in the early stage of diabetic nephropathy, however, the NO synthase inhibition has been shown to increase intraglomerular capillary pressure in experimental glomerulonephritis (15,16). The pathophysiological implication of ET in the glomerular circulation is not well understood. The kidney has abundant ability to produce prostaglandins (PG) from arachidonic acid and PGE2 which facilitates natriuresis and dilates the afferent arterioles is the major PG produced in the kidney. As compared with this, PGI2 produced by vascular endothelium dilates both the afferent and the efferent arterioles (17). Nonsteroidal anti-inflammatory drugs such as indomethacin, which inhibit cyclooxygenase and PG production, can cause renal dysfunction as the adverse effect. The inflammatory process in the pathogenesis of glomerulonephritis is supposed to stimulate PG production in the kidney. This possibly increases glomerular and renal blood flow on one hand, however, may rather increase intraglomerular pressure on the other hand by preferentially dilating the afferent arterioles. However, it has been reported that the long-term administration of PGI2 analogue mitigated the progression of renal dysfunction without increasing intraglomerular capillary pressure in patients with chronic glomerulonephritis (18).

Taken these together into consideration, it is suggested that the enhancement of RAA system is harmful to the glomeruli and the kidney via the nocuous actions of angiotensin II and aldosterone. Reductions in renal function generally cause an increase in body fluid volume which inhibits plasma renin activity and concentrations of angiotensin II and aldosterone. Therefore, the circulating components of RAA system is supposed to be rather suppressed in patients with advanced glomerulonephritis. However, the renal and cardiovascular cells have been shown to produce components of RAA system such as renin, angiotensin converting enzyme (ACE) and aldosterone. In addition, angiotensinogen produced by the liver is abundant in plasma. Therefore, it is thought that angiotensin II and aldosterone are locally produced in the renal and cardiovascular systems and their concentrations in the tissues may be higher than in plasma. And, it is possible that the renal tissue RAA system is rather enhanced and contributes to the progression of renal injuries in patients with advanced glomerulonephritis although the circulating components of RAA system are suppressed.

#### **4. Inhibitors of renin-angiotensin-aldosterone system in antihypertensive drug therapy for patients with glomerulonephritis**

The precedent sections stressed the importance of strict blood pressure control and the implications of RAA system in the management of renal diseases in order to prevent the progression of renal dysfunction efficiently and effectively. In this context, inhibitors of RAA system such as ACE inhibitors and angiotensin II receptor antagonists (ARB) are supposed to provide renoprotective effects in addition to their hypotensive effects by inhibiting the detrimental actions of angiotensin II and aldosterone. Especially, these inhibitors of RAA system preferentially dilate the efferent arterioles as compared to the

Several other hormones and autacoids are known to elicit dilation or contraction of the glomerular arterioles. Atrial natriuretic peptide (ANP), produced by the heart, dilates the afferent arteriole and preserves renal and glomerular blood flow in the state of heart failure (12). This action is supposed to work also in glomerulonephritis patients with reduced renal function because the plasma ANP level is increased by body fluid volume increase and reduced clearance in the kidney. Vascular endothelium produces vasoactive substances such as nitric oxide (NO) and endothelin (ET). NO preferentially dilates and ET preferentially contract the afferent arterioles (13,14). NO is supposed to participate in the mechanism of increased glomerular filtration in the early stage of diabetic nephropathy, however, the NO synthase inhibition has been shown to increase intraglomerular capillary pressure in experimental glomerulonephritis (15,16). The pathophysiological implication of ET in the glomerular circulation is not well understood. The kidney has abundant ability to produce prostaglandins (PG) from arachidonic acid and PGE2 which facilitates natriuresis and dilates the afferent arterioles is the major PG produced in the kidney. As compared with this, PGI2 produced by vascular endothelium dilates both the afferent and the efferent arterioles (17). Nonsteroidal anti-inflammatory drugs such as indomethacin, which inhibit cyclooxygenase and PG production, can cause renal dysfunction as the adverse effect. The inflammatory process in the pathogenesis of glomerulonephritis is supposed to stimulate PG production in the kidney. This possibly increases glomerular and renal blood flow on one hand, however, may rather increase intraglomerular pressure on the other hand by preferentially dilating the afferent arterioles. However, it has been reported that the long-term administration of PGI2 analogue mitigated the progression of renal dysfunction without increasing intraglomerular

Taken these together into consideration, it is suggested that the enhancement of RAA system is harmful to the glomeruli and the kidney via the nocuous actions of angiotensin II and aldosterone. Reductions in renal function generally cause an increase in body fluid volume which inhibits plasma renin activity and concentrations of angiotensin II and aldosterone. Therefore, the circulating components of RAA system is supposed to be rather suppressed in patients with advanced glomerulonephritis. However, the renal and cardiovascular cells have been shown to produce components of RAA system such as renin, angiotensin converting enzyme (ACE) and aldosterone. In addition, angiotensinogen produced by the liver is abundant in plasma. Therefore, it is thought that angiotensin II and aldosterone are locally produced in the renal and cardiovascular systems and their concentrations in the tissues may be higher than in plasma. And, it is possible that the renal tissue RAA system is rather enhanced and contributes to the progression of renal injuries in patients with advanced glomerulonephritis although the circulating components of RAA system are suppressed.

**4. Inhibitors of renin-angiotensin-aldosterone system in antihypertensive**

The precedent sections stressed the importance of strict blood pressure control and the implications of RAA system in the management of renal diseases in order to prevent the progression of renal dysfunction efficiently and effectively. In this context, inhibitors of RAA system such as ACE inhibitors and angiotensin II receptor antagonists (ARB) are supposed to provide renoprotective effects in addition to their hypotensive effects by inhibiting the detrimental actions of angiotensin II and aldosterone. Especially, these inhibitors of RAA system preferentially dilate the efferent arterioles as compared to the

capillary pressure in patients with chronic glomerulonephritis (18).

**drug therapy for patients with glomerulonephritis**

afferent arterioles and thereby lower intraglomerular capillary pressure effectively (Figure 5). Anderson et al. (19) have shown that an ACE inhibitor lowers intraglomerular capillary pressure, reduces proteinuria and inhibits the progression of glomerular sclerosis more prominently than other antihypertensive drugs in rats with reduced renal mass in which the circulating RAA system is thought to be suppressed.

In human, it is a distinctive feature that the intraglomerular capillary pressure is elevated and the GFR is increased at the early stage of diabetic nephropathy. This glomerular hypertension facilitates the progression of diabetic nephropathy stages, namely, microalbuminuria, overt proteinuria, a GFR reduction, a serum creatinine increase and end-stage renal failure. Taguma et al. (20) have first reported that an ACE inhibitor reduces proteinuria in patients with diabetic nephropathy, and it is suggested that the suppression of angiotensin II generation brings about alleviation of glomerular hypertension and reduce hydrauric transcapillary filtration pressure of protein. After that, Lewis et al. (21) performed the multi-center collaborative prospective study evaluating the renoprotective effects of an ACE inhibitor in patients with type 1 diabetes mellitus presenting overt proteinuria and demonstrated that captopril inhibited the serum creatinine increase and the incidence of end-stage renal failure. As well as ACE inhibitors, multiple lines of later clinical studies have indicated that ARB are effective in retarding the progression of nephropathy at each stage in patients with type 2 diabetes (22-24).

With regard to the non-diabetic renal disease such as glomerulonephritis, the ACE Inhibition in Progressive Renal Insufficiency (AIPRI) study (25) and Ramipril Efficacy in Nephropathy (REIN) study (26) showed that ACE inhibitors delay the progression of renal insufficiency in European patients with non-diabetic renal disease. Furthermore, African American Study of Kidney Disease and Hypertension (AASK) (27) suggested that ACE inhibitors slow renal disease progression in African American patients with hypertensive renal disease. Also as for the Asian population, we have reported that an ACE inhibitor and an ARB are effective in reducing proteinuria and slowing the deterioration of renal function in Japanese patients with chronic glomerulonephritis (28,29). Namely, an ACE inhibitor, benazepril, or an ARB, valsartan, inhibited the increase in serum creatinine and reduced proteinuria by 30-40% as compared with placebo (Figure 7,8). In addition, there is another study reported that an ACE inhibitor improved renal outcomes in Chinese patients with advanced stage of non-diabetic renal disease whose serum creatinine ranged 3.1 to 5.0mg/dL (30).

Fig. 7. Changes in serum creatinine concentrations and urinary protein excretions in glomerulonephritis patients given the ACE inhibitor or the placebo (28).

Blood Pressure Control in Patients with Glomerulonephritis 463

pressure is generally achieved only in less than a half of hypertensive patients under treatment. In terms of lowering blood pressure, the hypotensive effect of CCB, directly dilating vascular smooth muscle, is consistently reliable in various conditions including glomerulonephritis patients. Therefore, the addition of CCB to RAA system inhibitors is expected to bring about effective blood pressure reduction with few chances to cause

Ca channels residing in the plasma membrane of cells are composed five subunits; 1, 2, , and . Among them, the 1 subunit conforming Ca2+ ion pathway has isoforms of L, N, P/Q, R and T. There are three isoforms of 1 subunit, L, N and T in the cardiovascular tissues, and Table 1 shows their distributions, functions and pharmacological blockers. Dihydropyridine (DHP) CCB, which are generally used as hypertensive drugs, blocks the Ltype Ca channels existing in the arterial smooth muscle. With regard to the glomerular arterioles, because the afferent but not the efferent arterioles have the L-type channels, DHP CCB generally preferentially dilate the afferent arterioles. Therefore, it is supposed that the reduction in intraglomerular capillary pressure may not be so prominent as compared with the reduction in systemic arterial pressure. In this respect, the N-type and the T-type channels exist both in the afferent and the efferent arterioles and the blockers of these Ca channels are assumed to dilate both glomerular arterioles. This property is expected to contribute to the reduction in intraglomerular capillary pressure. Indeed, the N-type CCB, cilnidipine, and the T-type CCB such as efonidipine and azelnidipine have been shown to reduce proteinuria significantly in patients with glomerulonephritis as compared with Ltype CCB (Figure 9), suggesting these CCB are effective in alleviating glomerular

Fig. 9. The glomerular filtration rate (GFR) and the urinary excretions of protein in glomerulonephritis patients given the L-type Ca channel blocker (CCB), amlodipine,

As listed in Table 1, T-type Ca channels exist also in the adrenal and the in vitro experiments using cultured adrenal cells have shown that the T-type CCB suppress the expression of

or the L- and T-type CCB, efonidipine (35).

impeding adverse effects.

hypertension (34-36).

Fig. 8. Changes in serum creatinine concentrations and urinary protein excretions in glomerulonephritis patients given the angiotensin II receptor blocker (ARB) or the placebo (29).

As compared with ACE inhibitors and ARB, clinical evidence of other inhibitors of RAA system, such as renin inhibitors and aldosterone blockers seems less abundant regarding their renoprotecitve effects in patients with glomerulonephritis. In the cascade of RAA system indicated in Figure 6, conversion of angiotensinogen to angiotensin I by the enzymatic action of renin is assumed to be a rate-limiting step. Therefore, renin inhibitors such as aliskiren are thought to be theoretically effective in suppressing the activity of RAA system. Aliskiren, alone or in combination with ARB, has been shown to reduce albuminuria and proteinuria in patients with diabetic nephropathy (31,32), however, its efficacy in patients with glomerulonephritis is to be studied.

ACE inhibitors are widely used in the treatment of hypertension and renal disease. They reduce plasma levels of angiotensin II and aldosterone. However, it has been shown that the plasma aldosterone concentration rather increases in a certain portion of patients after month of long-term administration and this phenomenon is recognized as aldosterone breakthrough. Sato et al. (33) have reported that the long-term ACE inhibitor treatment failed to reduce albuminuria in patients with diabetic nephropathy who had developed aldosterone breakthrough, however, the albuminuria significantly reduced after adding spironolactone, an aldosterone blocker. Although spironolactone can cause adverse effects by its partially estrogenic actions such as gynecomastia and menstrual disorder which sometimes hamper the continuation of administration, eplerenone, a newly developed aldosterone blocker, is much more specific to the mineralocorticoid receptor and almost free from such estrogenic side effects. There is paucity of clinical evidence as to the effects of aldosterone blockers in glomerulonephritis patients, however, the use of an aldosterone blocker in addition to an ACE inhibitor or an ARB would be expected to exhibit protective effects against the progressions of glomerular injuries and renal dysfunction.

### **5. Calcium channel blockers in antihypertensive drug therapy for patients with glomerulonephritis**

Although the guidelines for hypertension management recommend strict blood pressure control in order to prevent organ injuries and cardiovascular diseases, the target blood

Fig. 8. Changes in serum creatinine concentrations and urinary protein excretions in

efficacy in patients with glomerulonephritis is to be studied.

glomerulonephritis patients given the angiotensin II receptor blocker (ARB) or the placebo (29). As compared with ACE inhibitors and ARB, clinical evidence of other inhibitors of RAA system, such as renin inhibitors and aldosterone blockers seems less abundant regarding their renoprotecitve effects in patients with glomerulonephritis. In the cascade of RAA system indicated in Figure 6, conversion of angiotensinogen to angiotensin I by the enzymatic action of renin is assumed to be a rate-limiting step. Therefore, renin inhibitors such as aliskiren are thought to be theoretically effective in suppressing the activity of RAA system. Aliskiren, alone or in combination with ARB, has been shown to reduce albuminuria and proteinuria in patients with diabetic nephropathy (31,32), however, its

ACE inhibitors are widely used in the treatment of hypertension and renal disease. They reduce plasma levels of angiotensin II and aldosterone. However, it has been shown that the plasma aldosterone concentration rather increases in a certain portion of patients after month of long-term administration and this phenomenon is recognized as aldosterone breakthrough. Sato et al. (33) have reported that the long-term ACE inhibitor treatment failed to reduce albuminuria in patients with diabetic nephropathy who had developed aldosterone breakthrough, however, the albuminuria significantly reduced after adding spironolactone, an aldosterone blocker. Although spironolactone can cause adverse effects by its partially estrogenic actions such as gynecomastia and menstrual disorder which sometimes hamper the continuation of administration, eplerenone, a newly developed aldosterone blocker, is much more specific to the mineralocorticoid receptor and almost free from such estrogenic side effects. There is paucity of clinical evidence as to the effects of aldosterone blockers in glomerulonephritis patients, however, the use of an aldosterone blocker in addition to an ACE inhibitor or an ARB would be expected to exhibit protective

effects against the progressions of glomerular injuries and renal dysfunction.

**with glomerulonephritis**

**5. Calcium channel blockers in antihypertensive drug therapy for patients**

Although the guidelines for hypertension management recommend strict blood pressure control in order to prevent organ injuries and cardiovascular diseases, the target blood pressure is generally achieved only in less than a half of hypertensive patients under treatment. In terms of lowering blood pressure, the hypotensive effect of CCB, directly dilating vascular smooth muscle, is consistently reliable in various conditions including glomerulonephritis patients. Therefore, the addition of CCB to RAA system inhibitors is expected to bring about effective blood pressure reduction with few chances to cause impeding adverse effects.

Ca channels residing in the plasma membrane of cells are composed five subunits; 1, 2, , and . Among them, the 1 subunit conforming Ca2+ ion pathway has isoforms of L, N, P/Q, R and T. There are three isoforms of 1 subunit, L, N and T in the cardiovascular tissues, and Table 1 shows their distributions, functions and pharmacological blockers. Dihydropyridine (DHP) CCB, which are generally used as hypertensive drugs, blocks the Ltype Ca channels existing in the arterial smooth muscle. With regard to the glomerular arterioles, because the afferent but not the efferent arterioles have the L-type channels, DHP CCB generally preferentially dilate the afferent arterioles. Therefore, it is supposed that the reduction in intraglomerular capillary pressure may not be so prominent as compared with the reduction in systemic arterial pressure. In this respect, the N-type and the T-type channels exist both in the afferent and the efferent arterioles and the blockers of these Ca channels are assumed to dilate both glomerular arterioles. This property is expected to contribute to the reduction in intraglomerular capillary pressure. Indeed, the N-type CCB, cilnidipine, and the T-type CCB such as efonidipine and azelnidipine have been shown to reduce proteinuria significantly in patients with glomerulonephritis as compared with Ltype CCB (Figure 9), suggesting these CCB are effective in alleviating glomerular hypertension (34-36).

Fig. 9. The glomerular filtration rate (GFR) and the urinary excretions of protein in glomerulonephritis patients given the L-type Ca channel blocker (CCB), amlodipine, or the L- and T-type CCB, efonidipine (35).

As listed in Table 1, T-type Ca channels exist also in the adrenal and the in vitro experiments using cultured adrenal cells have shown that the T-type CCB suppress the expression of

Blood Pressure Control in Patients with Glomerulonephritis 465

Strict blood pressure control over 24 hours is of primary importance in preventing progression of renal injuries and deterioration of renal function in patients with glomerular diseases. In addition, it is important to lower not only systemic blood pressure but also intraglomerular capillary pressure in order to protect glomeruli from sclerosis because the increase in intraglomerular capillary pressure, glomerular hypertension, causes filtration of albuminuria and proteinuria which are dose-dependently related to the progression of renal injuries. Therefore, the antihypertensive therapy in patients with glomerulonephritis should aim not only the normalization of blood pressure but also the reduction of proteinuria and albuminuria. In order to lower intraglomerular capillary pressure, inhibitors of RAA system such as ACE inhibitors and ARB are effective as antihypertensive drugs because angiotensin II greatly contribute to the contraction of the efferent arterioles of glomeruli. In addition, interests are attracted as to the usefulness aldosterone receptor blockers and renin inhibitors as novel agents protecting the kidney. CCB are potent hypotensive agents, however, they rather dilate the afferent arterioles and may not be so effective as RAA system inhibitors in lowering intraglomerular capillary pressure. In this respect, some dihydropyridine CCB which block not only L-type Ca channel but also N- or T-type Ca channel have been shown to dilate efferent arterioles in addition to dilating afferent arterioles and are expected to be

beneficial to protect glomeruli as well as lowering blood pressure effectively.

and the adequate blood pressure control is a pivotally important issue.

Prognosis of renal function in glomerulonephritis may be largely dependent on the nature of its pathohistological diagnosis and the therapeutic effects of immunosuppressive agents. In addition to these, efforts to lessen and minimize risk factors for renal injuries should be continuously made in order to inhibit the deterioration of renal function. Such efforts would be expected to contribute to inhibit not only the development of renal failure but also the incidence of cardiovascular diseases and to improve the prognosis of glomerulonephritis patients. Among the various risk factors for real injuries hypertension has great influence

[1] Tozawa M, Iseki K, Iseki C, Kinjo K, Ikemiya Y, Takishita S. Blood pressure predicts risk

[2] Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S,

[3] Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J,

[4] National Heart, Lung, and Blood Institute Joint National Committee on Prevention,

of developing end-stage renal disease in men and women. Hypertension 2003; 41:

Massry SG, Seifter JL. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med

Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000; 36: 646-

Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the

**6. Summary and conclusions**

**7. References**

1341-1345.

661.

1995; 123: 754-762.

aldosterone synthase gene (CYP11B2) and production of aldosterone (37,38). In harmony with this, clinical studies in healthy subjects and hypertensive patients have shown that the acute or the chronic administrations of T-type CCB lower plasma aldosterone levels (39,40). We have compared the effects of L- and T-type CCB efonidipine and L-type CCB amlodipine in patients with glomerulonephritis and observed that efonidipine reduces plasma aldosterone concentration as compared with amlodipine while the plasma angiotensin II concentrations were comparable (Figure 10)(35). It is mentioned in the previous section of this chapter that aldosterone is supposed to promote the progression of glomerular injuries and the aldosterone blocker can reduce albuminuria. Considering that the mechanism of aldosterone suppression by T-type CCB is different from those by ACE inhibitors, ARB and aldosterone blockers, this property of T-type CCB would be expected to provide an additive benefit, when combined with the RAA system inhibitors, against the progression of renal dysfunction in the antihypertensive treatment of glomerulonephritis patients.

Table 1. Subtypes of Ca channel and their locations, functions and blockers.

Fig. 10. The plasma concentrations of angiotensin II and aldosterone in glomerulonephritis patients given the L-type Ca channel blocker (CCB), amlodipine, or the L- and T-type CCB, efonidipine (35).

### **6. Summary and conclusions**

464 An Update on Glomerulopathies – Clinical and Treatment Aspects

aldosterone synthase gene (CYP11B2) and production of aldosterone (37,38). In harmony with this, clinical studies in healthy subjects and hypertensive patients have shown that the acute or the chronic administrations of T-type CCB lower plasma aldosterone levels (39,40). We have compared the effects of L- and T-type CCB efonidipine and L-type CCB amlodipine in patients with glomerulonephritis and observed that efonidipine reduces plasma aldosterone concentration as compared with amlodipine while the plasma angiotensin II concentrations were comparable (Figure 10)(35). It is mentioned in the previous section of this chapter that aldosterone is supposed to promote the progression of glomerular injuries and the aldosterone blocker can reduce albuminuria. Considering that the mechanism of aldosterone suppression by T-type CCB is different from those by ACE inhibitors, ARB and aldosterone blockers, this property of T-type CCB would be expected to provide an additive benefit, when combined with the RAA system inhibitors, against the progression of renal dysfunction in the

Ca channel Tissue distribution Function Blocker

vasocontraction intestinal contraction

facilitation of signal

vasocontraction stimulation of excitement conduction aldosterone secretion

transmission cilnidipine

nifedipine nicardipine nitrendipine amlodipine etc.

manidipine efonidipine benidipine azelnidipine mibefradil

antihypertensive treatment of glomerulonephritis patients.

intestinal smooth muscle

nerve end

vascular smooth muscle cardiac muscle adrenal

Table 1. Subtypes of Ca channel and their locations, functions and blockers.

Fig. 10. The plasma concentrations of angiotensin II and aldosterone in glomerulonephritis patients given the L-type Ca channel blocker (CCB), amlodipine, or the L- and T-type CCB,

L-type vascular smooth muscle

N-type brain

T-type

efonidipine (35).

Strict blood pressure control over 24 hours is of primary importance in preventing progression of renal injuries and deterioration of renal function in patients with glomerular diseases. In addition, it is important to lower not only systemic blood pressure but also intraglomerular capillary pressure in order to protect glomeruli from sclerosis because the increase in intraglomerular capillary pressure, glomerular hypertension, causes filtration of albuminuria and proteinuria which are dose-dependently related to the progression of renal injuries. Therefore, the antihypertensive therapy in patients with glomerulonephritis should aim not only the normalization of blood pressure but also the reduction of proteinuria and albuminuria. In order to lower intraglomerular capillary pressure, inhibitors of RAA system such as ACE inhibitors and ARB are effective as antihypertensive drugs because angiotensin II greatly contribute to the contraction of the efferent arterioles of glomeruli. In addition, interests are attracted as to the usefulness aldosterone receptor blockers and renin inhibitors as novel agents protecting the kidney. CCB are potent hypotensive agents, however, they rather dilate the afferent arterioles and may not be so effective as RAA system inhibitors in lowering intraglomerular capillary pressure. In this respect, some dihydropyridine CCB which block not only L-type Ca channel but also N- or T-type Ca channel have been shown to dilate efferent arterioles in addition to dilating afferent arterioles and are expected to be beneficial to protect glomeruli as well as lowering blood pressure effectively.

Prognosis of renal function in glomerulonephritis may be largely dependent on the nature of its pathohistological diagnosis and the therapeutic effects of immunosuppressive agents. In addition to these, efforts to lessen and minimize risk factors for renal injuries should be continuously made in order to inhibit the deterioration of renal function. Such efforts would be expected to contribute to inhibit not only the development of renal failure but also the incidence of cardiovascular diseases and to improve the prognosis of glomerulonephritis patients. Among the various risk factors for real injuries hypertension has great influence and the adequate blood pressure control is a pivotally important issue.

#### **7. References**

Blood Pressure Control in Patients with Glomerulonephritis 467

[19] Anderson S, Rennke HG, Brenner BM. Therapeutic advantage of converting enzyme

[20] Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, Ishizaki M, Takahashi H, Sekino

[21] Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-

[22] Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC,

[23] Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G,

[24] Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P;

[25] Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E,

[26] The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline

[27] Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, Charleston J, Cheek

[28] Ishimitsu T, Akashiba A, Kameda T, Takahashi T, Ohta S, Yoshii M, Minami J, Ono H,

patients with non-diabetic renal disease. Nephrology 2007; 12: 294-298. [29] Ishimitsu T, Kameda T, Akashiba A, Takahashi T, Ando N, Ohta S, Yoshii M, Inada H,

Numabe A, Matsuoka H. Benazepril slows progression of renal dysfunction in

Tsukada K, Minami J, Ono H, Matsuoka H. Effects of valsartan on the progression of chronic renal insufficiency in patients with nondiabetic renal diseases.

hypertension in the rat. J Clin Invest 1986; 77: 1993-2000.

type 2 diabetes. N Engl J Med 2001; 345: 851-860.

nephropathy. N Engl J Med. 200; 345: 861-869.

with type 2 diabetes. N Engl J Med 2001; 345: 870-878.

diabetic nephropathy. Lancet 1997; 349: 1857-1863.

Med 1985; 313: 1617-1620.

1996; 334: 939-945.

2001; 285: 2719-2728.

Hypertens Res 2005; 28: 865-870.

Engl J Med 1993; 329: 1456-1462.

inhibitors in arresting progressive renal disease associated with systemic

H, Sasaki Y. Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl J

enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N

Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to

Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and

Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients

Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med

in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-

D, Cleveland W, Douglas JG, Douglas M, Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Y, Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J, Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, Middleton J, Miller ER 3rd, Norris K, O'Connor D, Ojo A, Phillips RA, Pogue V, Rahman M, Randall OS, Rostand S, Schulman G, Smith W, Thornley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA

Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560-2572.

High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560-2572. [5] The task Force for the Management of Arterial Hypertension of the European Society of

2009). Hypertens Res 2009; 32: 3-107.

Nephrol 2001; 12: 1315-1325.

J Med Sci 2003; 326: 15-24.

1994; 4: 1847-1854.

and disease.Pharmacol Ther 2001; 90: 61-88.

arterioles. Am J Physiol 1985; 248: F779-F784.

of diabetic nephropathy. Diabetologia 1998; 41: 1426-1434.

S57-S65.

Management of Arterial Hypertension. J Hypertens 2007;25: 1105-1187. [6] Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M, Imai Y, Imaizumi T,

[7] Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration

[8] Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature

[9] Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone

[10] Brewster UC, Setaro JF, Perazella MA. The renin-angiotensin-aldosterone system:

[11] Rafiq K, Hitomi H, Nakano D, Nishiyama A. Pathophysiological roles of aldosterone and mineralocorticoid receptor in the kidney. J Pharmacol Sci 2011; 115: 1-7. [12] Lanese DM, Yuan BH, Falk SA, Conger JD. Effects of atriopeptin III on isolated rat afferent and efferent arterioles. Am J Physiol. 1991; 261: F1102-F1109. [13] Patzak A, Lai E, Persson PB, Persson AE. Angiotensin II-nitric oxide interaction in glomerular arterioles. Clin Exp Pharmacol Physiol 2005; 32: 410-414. [14] Naicker S, Bhoola KD. Endothelins: vasoactive modulators of renal function in health

[15] Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K, Wada J,

[16] Ferrario R, Takahashi K, Fogo A, Badr KF, Munger KA. Consequences of acute nitric

[17] Edwards RM. Effects of prostaglandins on vasoconstrictor action in isolated renal

[18] Fujita T, Fuke Y, Satomura A, Hidaka M, Ohsawa I, Endo M, Komatsu K, Ohi H. PGl2

insufficiency. Prostaglandins Leukot Essent Fatty Acids 2001; 65: 223-227.

Makino H. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration

oxide synthesis inhibition in experimental glomerulonephritis. J Am Soc Nephrol

analogue mitigates the progression rate of renal dysfunction improving renal blood flow without glomerular hyperfiltration in patients with chronic renal

intrinsic renal disease. N Engl J Med 1982; 307: 652-659.

Joint National Committee on Prevention, Detection, Evaluation, and Treatment of

Hypertension and European Society of Cardiology. 2007 Guidelines for the

Ito S, Iwao H, Kario K, Kawano Y, Kim-Mitsuyama S, Kimura G, Matsubara H, Matsuura H, Naruse M, Saito I, Shimada K, Shimamoto K, Suzuki H, Takishita S, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, Ueshima H, Umemura S, Ishimitsu T, Rakugi H; Japanese Society of Hypertension Committee. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH

in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc

of kidney disease. The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and

system in the progression of chronic kidney disease. Kidney Int Suppl 2005; 99:

cardiorenal effects and implications for renal and cardiovascular disease states. Am

[30] Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang

[31] Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, Danser AH,

[32] Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study

[33] Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in

[34] Fujita T, Ando K, Nishimura H, Ideura T, Yasuda G, Isshiki M, Takahashi K;

[35] Ishimitsu T, Kameda T, Akashiba A, Takahashi T, Ohta S, Yoshii M, Minami J, Ono H,

[37] Tanaka H, Shigenobu K. Pathophysiological significance of T-type Ca2+ channels: Ttype Ca2+ channels and drug development. J Pharmacol Sci 2005; 99: 214-220. [38] Imagawa K, Okayama S, Takaoka M, Kawata H, Naya N, Nakajima T, Horii M,

[39] Okayama S, Imagawa K, Naya N, Iwama H, Somekawa S, Kawata H, Horii M,

[40] Tanaka T, Tsutamoto T, Sakai H, Fujii M, Yamamoto T, Horie M. Comparison of the

patients with diabetic nephropathy. Hypertension 2003; 41: 64-68.

patients with chronic renal disease. Kidney Int 2007; 72: 1543-1549.

insufficiency. N Engl J Med 2006; 354: 131-40.

albuminuria. Diabetes Care 2009; 32: 1873-1879.

nephropathy. N Engl J Med 2008; 358: 2433-2446.

Sci 2007; 333: 321-326.

47: 133-138.

2006; 29: 493-497.

Hypertens Res 2007; 30: 691-697.

GB, Liu ZR, Geng RW. Efficacy and safety of benazepril for advanced chronic renal

Boomsma F, Frandsen E, Parving HH. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and

Investigators. Aliskiren combined with losartan in type 2 diabetes and

Cilnidipine versus Amlodipine Randomised Trial for Evaluation in Renal Desease(CARTER) Study Investigators. Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive

Numabe A, Matsuoka H. Efonidipine reduces proteinuria and plasma aldosterone in patients with chronic glomerulonephritis. Hypertens Res 2007; 30: 621-626. [36] Nakamura T, Sugaya T, Kawagoe Y, Suzuki T, Ueda Y, Koide H, Inoue T, Node K.

Azelnidipine reduces urinary protein excretion and urinary liver-type fatty acid binding protein in patients with hypertensive chronic kidney disease. Am J Med

Uemura S, Saito Y. Inhibitory effect of efonidipine on aldosterone synthesis and secretion in human adrenocarcinoma (H295R) cells. J Cardiovasc Pharmacol 2006;

Nakajima T, Uemura S, Saito Y. Blocking T-type Ca2+ channels with efonidipine decreased plasma aldosterone concentration in healthy volunteers. Hypertens Res

effects of efonidipine and amlodipine on aldosterone in patients with hypertension.

## *Edited by Sharma S. Prabhakar*

An Update on Glomerulopathies - Clinical and Treatment Aspects is a systemic overview of recent advances in clinical aspects and therapeutic options in major syndromes of glomerular pathology. The book contains twenty four chapters divided conveniently into five sections. The first section deals with primary glomerulopathies, and the second section is devoted to glomerulopathies complicating infectious conditions. The third section deals with systemic autoimmune disorders and vasculitides which constitute major causes of glomerular disease and often renal failure. The fourth section includes chapters discussing the glomerular involvement in some major metabolic and systemic conditions. The final section has chapters which relate to some general aspects of glomerular diseases. This book will form an excellent reference tool for practicing and academic nephrology community.

An Update on Glomerulopathies - Clinical and Treatment Aspects

An Update on

Glomerulopathies

*Edited by Sharma S. Prabhakar*

Photo by HYWARDS / iStock