Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy.

BACKGROUND: Complement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia. METHODS: In this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up. RESULTS: A total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (<1 month) was noted in six patients, whereas recurrence in five patients occurred within 8-17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died. CONCLUSION: Post-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.

Contribution of Clinically Indicated Repeat Renal Biopsy in Indian Patients with Lupus Nephritis.

BACKGROUND: Repeat renal biopsy is usually done for lupus nephritis (LN) flare or resistant disease. We analyzed the changes between first and repeat biopsy and the contribution of repeat biopsy on renal outcome in LN patients. METHODS: This was a retrospective study carried out at a tertiary care center in India. Sixty-two LN patients who underwent repeat biopsy for clinical indications, between January 2012 to December 2016, were included. Clinical and histological parameters at first and second biopsies were compared. Logistic regression analysis was done to determine parameters on repeat biopsy predicting response at last visit. RESULTS: Repeat biopsy was done for relapse in 56% and for resistant disease in 44% patients. Seven (13.7%) out of 51 patients with baseline proliferative histology converted to non-proliferative lesion on second biopsy, while 2 (18.2%) out of 11 with baseline non-proliferative lesion converted to proliferative lesion on second biopsy. On repeat biopsy, the presence of endocapillary proliferation decreased, whereas glomerulosclerosis, interstitial fibrosis/tubular atrophy (IFTA), and glomerular basement membrane thickening increased. At the last visit (median follow-up of 38.6 months after first biopsy and 13.8 months after second biopsy), 79% of patients were in remission and 6.5% needed renal replacement therapy. The presence of IFTA >30% and thrombotic microangiopathy (TMA) on second biopsy independently predicted response at last visit. CONCLUSION: In Indian patients with LN, chronicity markers and superimposed membranous pattern increased on repeat biopsy done for clinical indications. The presence of IFTA and TMA on second biopsy predicted response at last visit.

Gastrointestinal Involvement in Granulomatosis with Polyangiitis: Case Report and Review.

Granulomatosis with polyangiitis (GPA) commonly affects upper/lower respiratory tract and kidneys. It causes necrotizing vasculitis of small and medium-sized blood vessels. Gastrointestinal (GI) involvement is an uncommon manifestation of GPA, and presentation with predominant GI manifestation is noteworthy. We report a case of 50-year-old male with melena due to GI vasculitis along with other systemic involvement. The patient was treated with pulse methylprednisolone, cyclophosphamide, and plasmapheresis. To manage the refractory GI bleed, the patient underwent surgical resection, and the histology of the surgical specimen confirmed necrotizing vasculitis.

Postpartum Renal Cortical Necrosis Is Associated With Atypical Hemolytic Uremic Syndrome in Developing Countries.

INTRODUCTION: Pregnancy-related acute kidney injury is the most common cause of renal cortical necrosis (RCN). Atypical hemolytic uremic syndrome (aHUS) as a cause of RCN in pregnant/postpartum is underevaluated. In the current article, we describe a series of cases of pregnancy-related RCN. METHODS: All cases with acute kidney injury (AKI) in the setting of pregnancy and postpartum state were included. Diagnosis of RCN was made by contrast-enhanced computerized tomography (nonenhancing renal cortex, enhancing medulla, and no excretion of contrast medium) or on a renal biopsy. aHUS was diagnosed in the presence of microangiopathic hemolytic anemia (thrombocytopenia, elevated lactate dehydrogenase with schistocytes on peripheral smear examination, or low haptoglobin). RESULTS: A total of 21 (17.5%) patients presented with RCN during pregnancy, all in the postpartum state. Twenty patients (95.2%) showed microangiopathic hemolytic anemia consistent with HUS and 1 (4.8%) patient had biopsy-proven thrombotic microangiopathy. Low complement 3 or activation of an alternate complement pathway was seen in 9 of 15 patients in which it was done. At the end of 6 months, only 2 (9.5%) patients had partial recovery of renal functions, 5 (23.8%) patients died, and 14 remained (66.7%) on hemodialysis. CONCLUSION: The clinical and laboratory features are highly suggestive of aHUS in more than three-fourths of cases with postpartum RCN. Investigations are needed to look for genetic abnormalities in the complement pathway.

Persistent CD-19 depletion by rituximab is cost-effective in maintaining remission in calcineurin-inhibitor dependent podocytopathy.

AIM: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent or steroid resistant, requiring long-term calcineurin inhibitors (CNI) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI-dependent patients. METHODS: This was a prospective observational study conducted from July 2014 to February 2018. Steroid-dependent nephrotic syndrome or steroid-resistant nephrotic syndrome (biopsy proven MCD/FSGS), who were CNI dependent were enrolled. Mean age at enrolment was 22.77 ± 7.45 years. All patients received rituximab at a dose of 375 mg/m2 at entry in the study. CD-19 levels were monitored monthly and patients having CD-19 levels >5/µL and/or > 1% received additional low-dose (100 mg) of rituximab. RESULTS: A total of 24 patients were followed up for 12 months. At the end of 6 and 12 months, 87.5% and 79.16% of the patients achieved remission, respectively. Eight (33.33%) patients developed relapse. The mean dose of rituximab in the first year was 791 mg. The average cost of rituximab in the first year was 487.17$. Rituximab was well-tolerated, with mild infusion reactions, respiratory tract infection and oral candidiasis in 5 (20.83%), 5 (20.83%) and 1 (4.17%) patient, respectively. CONCLUSIONS: CD-19 targeted rituximab is a safe and cost-effective agent in remission maintenance in adults with CNI dependent. Over three-fourths of the patients with CNI-dependent podocytopathy maintain clinical remission with CD-19 targeted rituximab therapy.

Membranous nephropathy with light chain restricted deposits.

The literature on membranous nephropathy (MN) with monoclonal deposits on immunofluorescence (IF) and their outcome is very scarce. We report our experience of managing five patients with this clinical entity. The mean age of the patients was 33.2 ± 6.55 years. The mean proteinuria, serum albumin and serum creatinine was 5.73 ± 2.17 g/day, 2.86 ± 0.51 g/dL and 1.34 ± 1.19 mg/dL, respectively. None of the patients had a lymphoproliferative disorder. Only one patient had an elevated free light chain ratio. Four (80%) patients were M-type phospholipase A2 receptor (PLA2R) negative (tissue and serum), and one (20%) was PLA2R related. Three (60%) cases had monoclonal IgG3/k, one IgG3/λ, whereas one patient with PLA2R positivity had an IgG3/IgG4k subtype. Two (67%) patients treated with cyclical cyclophosphamide and steroids (cCYC/GC) achieved complete remission and one patient (33%) with elevated baseline creatinine had a reduction in serum creatinine with persistent proteinuria at the end of the 12th month of follow-up. One patient with PLA2R positive MN was treated with Rituximab and is in complete remission. The patient with an elevated free light chain at baseline was treated with Bortezomib/Thalidomide/Dexamethasone, had complete remission at 12 months, however, had a progressive rise in creatinine over the next 40 months of follow-up. The current series, though limited by numbers, documents the efficacy of conventional therapies in non-malignant associated MN with monoclonal deposits on IF.

Existing creatinine-based equations overestimate glomerular filtration rate in Indians.

BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important for diagnosis and risk stratification in chronic kidney disease and for selection of living donors. Ethnic differences have required correction factors in the originally developed creatinine-based GFR estimation equations for populations around the world. Existing equations have not been validated in the vegetarian Indian population. We examined the performance of creatinine and cystatin-based GFR estimating equations in Indians. METHODS: GFR was measured by urinary clearance of inulin. Serum creatinine was measured using IDMS-traceable Jaffe's and enzymatic assays, and cystatin C by colloidal gold immunoassay. Dietary protein intake was calculated by measuring urinary nitrogen appearance. Bias, precision and accuracy were calculated for the eGFR equations. RESULTS: A total of 130 participants (63 healthy kidney donors and 67 with CKD) were studied. About 50% were vegetarians, and the remainder ate meat 3.8 times every month. The average creatinine excretion were 14.7 mg/kg/day (95% CI: 13.5 to 15.9 mg/kg/day) and 12.4 mg/kg/day (95% CI: 11.2 to 13.6 mg/kg/day) in males and females, respectively. The average daily protein intake was 46.1 g/day (95% CI: 43.2 to 48.8 g/day). The mean mGFR in the study population was 51.66 ± 31.68 ml/min/1.73m2. All creatinine-based eGFR equations overestimated GFR (p < 0.01 for each creatinine based eGFR equation). However, eGFR by CKD-EPICys was not significantly different from mGFR (p = 0.38). The CKD-EPICys exhibited lowest bias [mean bias: -3.53 ± 14.70 ml/min/1.73m2 (95% CI: -0.608 to -0.98)] and highest accuracy (P30: 74.6%). The GFR in the healthy population was 79.44 ± 20.19 (range: 41.90-134.50) ml/min/1.73m2. CONCLUSION: Existing creatinine-based GFR estimating equations overestimate GFR in Indians. An appropriately powered study is needed to develop either a correction factor or a new equation for accurate assessment of kidney function in the Indian population.

Assessment of Liver Fibrosis by Transient Elastography Should Be Done After Hemodialysis in End Stage Renal Disease Patients with Liver Disease.

BACKGROUND AND AIMS: The patients with end stage renal disease (ESRD) are at greater risk of acquiring chronic hepatitis B or C and subsequently development of liver disease. The aim of the study was to assess liver fibrosis by transient elastography (TE) and look for factors associated with change in liver stiffness measurement (LSM) with one session of hemodialysis (HD). METHODS: Consecutive ESRD patients on maintenance hemodialysis (MHD) with suspected liver disease were enrolled. They underwent LSM by TE before and after one session of HD. Bioelectric impedance analysis was done to evaluate the volume status at the time of TE. RESULTS: Sixty-eight patients with mean age of 40 ± 14 years were included. There was a significant reduction in LSM after HD (18.5 [95% CI 14.8-23.1] vs. 11.2 [95% CI 8.8-13.7] kPa, p < 0.001), with a mean LSM reduction of 7.2 [95% CI 5.25-9.19] kPa. On stratification in two groups by net ultrafiltration during HD (> or < 2.5 liters [L]), change in LSM was substantially higher in patients when total fluid removed was > 2.5 L (8.6 [95% CI 5.7-11.5] vs. 5.1 [95% CI 2.9-7.5], p = 0.05). In 18 patients who underwent liver biopsy, LSM after HD performed better at detecting significant fibrosis, with area under receiver operating characteristics curve 0.71 [95% CI 0.46-0.97], versus 0.64 [95% CI 0.38-0.90], respectively. An LSM value of 12.2 kPa after HD was 71% sensitive and 74% specific for detection of significant fibrosis (≥ F2), while values less than 9 kPa ruled out significant fibrosis with a sensitivity and specificity of 37 and 100%, respectively. CONCLUSION: LSM by TE decreases significantly after HD in patients with ESRD on long-term MHD. Hence, TE should be done after HD for accurate assessment of liver fibrosis.

Rhino-orbital-cerebral zygomycosis in solid organ transplant recipients.

BACKGROUND: Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed. METHODS: SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included. RESULTS: Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04-1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02-0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01-0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease. CONCLUSIONS: Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes.

Central nervous system cryptococcosis in solid organ transplant recipients: clinical relevance of abnormal neuroimaging findings.

BACKGROUND: Prognostic implications of cryptococcal antigen and outcomes associated with central nervous system (CNS) cryptococcal lesions in solid organ transplant recipients have not been fully defined. METHODS: Patients were derived form a cohort of 122 solid organ transplant recipients with cryptococcosis in a multicenter study from 1999 to 2006. RESULTS: Central nervous system cryptococcosis was documented in 61 patients. Serum or cerebral spinal fluid antigen titers did not correlate with mortality at 90 days or cerebral spinal fluid sterilization at 2 weeks. Central nervous system lesions were identified in 16 patients and included leptomeningeal lesions in eight, parenchymal lesions in six, and hydrocephalus in two. Overall, 13/16 CNS lesions were present at the time of diagnosis. One parenchymal and two hydrocephalus lesions, however, developed after diagnosis and fulfilled the criteria for immune reconstitution syndrome. Cerebral spinal fluid antigen titers were higher with meningeal versus parenchymal lesions, and hydrocephalus (P=0.015). Mortality was 50% (3/6) for patients with parenchymal, 12.5% (1/8) for those with leptomeningeal, and 0/3 for patients with hydrocephalus. Mortality was 31% (4/13) for patients with CNS lesions at baseline and 0/3 in those with new onset lesions. CONCLUSIONS: Despite a higher antigen titer with meningeal lesions, outcomes tended to be worse with parenchymal compared with meningeal lesions or hydrocephalus. New onset CNS lesions may represent immune reconstitution syndrome and seemed to be associated with better outcome.

Pulmonary cryptococcosis in solid organ transplant recipients: clinical relevance of serum cryptococcal antigen.

BACKGROUND: The role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined. METHODS: We conducted a prospective, multicenter study of SOT recipients with pulmonary cryptococcosis during 1999-2006. RESULTS: Forty (83%) of 48 patients with pulmonary cryptococcosis tested positive for cryptococcal antigen. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen test result (P=.018), and antigen titers were higher in patients with extrapulmonary disease (P=.003) or fungemia (P=.045). Patients with single nodules were less likely to have a positive antigen test result than were those with all other radiographic presentations (P=.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen test results than were recipients of other types of SOT (P=.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than as pleural effusions and infiltrates (P=.008). CONCLUSIONS: A positive serum cryptococcal antigen test result in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease.

Rapidly progressive renal failure in type 2 diabetes in the tropical environment: a clinico-pathological study.

BACKGROUND: Rapid decline of renal function in a diabetic suggests the presence of a nondiabetic kidney disease (NDKD). We designed a prospective study to evaluate the factors associated with a rapid decline in renal function in patients with type 2 diabetes. METHODS: Over a 2 and a half year period, all patients with type 2 diabetes who presented with documented doubling of serum creatinine in less than 4 weeks or recently diagnosed advanced renal failure were identified. Patients with prerenal causes, urinary tract obstruction, or systemic disease causing renal failure were not included. Renal histology was studied in all cases. RESULTS: A total of 26 patients satisfied the inclusion criteria. Over 75% had serum creatinine >4 mg/dL at presentation and 62% were dialysis dependent. Renal histology showed mixed lesions of diabetic nephropathy (DN) and NDKD in 11 cases, only DN in nine, and pure NDKD in six. Diffuse proliferative glomerulonephritis (DPGN) was the commonest NDKD (27% cases), all on a background of DN. History of preceding cutaneous or pharyngeal infection was available in five cases. The proportion of postinfectious glomerulonephritis in diabetics with rapidly progressive renal failure was over six times that of the nondiabetic adult RPRF population during the study period. Four patients had acute interstitial nephritis and three showed crescentic glomerulonephritis. Other lesions included amyloidosis, atheroembolic disease, and renal papillary necrosis (one each). The frequency of microscopic hematuria and retinopathy was similar in those with pure DN and NDKD. Four out of seven cases with DPGN showed partial recovery whereas the other three remained unchanged. CONCLUSIONS: About two-thirds of patients with type 2 diabetes presenting with rapid decline of renal function in a tropical environment show NDKD. The high incidence of postinfectious glomerulonephritis in this group is possibly related to the high prevalence of skin and soft tissue infections; and could contribute to progressive kidney disease.

Acute renal failure due to cast nephropathy in nonsecretory myeloma: a case report and review of the literature.

Multiple myeloma is characterized by marrow plamacytsois, M spike in serum or urine electrophoresis and skeletal lytic lesions. The M spike may be absent in rare instances. We describe a case of myeloma cast nephropathy with acute renal failure who did not exhibit an M spike. lambda-chain staining was documented on immunoperoxidase, suggesting paraprotein-related tubular damage.

An unusual case of recurrence of AA amyloidosis in the renal allograft.

Recurrence of amyloidosis secondary to chronic infections in the renal allograft is highly unusual. We report the recurrence of amyloid in the graft within one year after transplantation in a patient with systemic AA amyloidosis secondary to tuberculosis. The diagnosis of tuberculosis was made in the immediate post-transplant period on the basis of good therapeutic response of fever and chest infiltrates to anti-tubercular chemotherapy.

Respiratory paralysis in Sjogren syndrome with normal renal function.

We report a 28-year-old woman who presented with quadriparesis and respiratory failure, and had severe hypokalaemia and distal renal tubular acidosis. She recovered completely on potassium and alkali supplementation. Biopsy and scintigraphy of the minor salivary glands confirmed the presence of Sjogren syndrome. A 6-month course of prednisolone did not correct the distal renal tubular acidosis.

Vesicoureteric reflux and reflux nephropathy as seen at a tertiary care adult nephrology service in India--an analysis of 86 patients.

Clinical features and risk factors for renal failure in patients with reflux nephropathy (RN) as seen in an adult nephrology service are likely to be different than those seen in a pediatric service. There are only a few studies on adults with vesicoureteric reflux (VUR) and RN and data on RN as seen in developing countries is still evolving. Retrospective analysis of records of patients diagnosed to have VUR by conventional micturating cystourethrogram over a 13 year period, as seen in the adult nephrology services of this tertiary care hospital in north India was carried out. Results are presented as mean +/- 2 SD. Unpaired t-test was used to compare means, chi-square test to define associations, and logistic regression analysis was done to define risk factors. Out of 86 patients diagnosed to have VUR, 69 (80.2%) were males and 22 (25.6%) were children. The mean age at presentation was 24.3 +/- 14.5 years and at onset of symptoms was 19.64 +/- 14.8 years. Sixty-nine (80.2%) patients had chronic renal failure (CRF) at presentation, including 33 (38.4%) patients who already had end stage renal failure (ESRF) at presentation in whom reflux was diagnosed during routine pretransplant evaluation and these constituted 5.5% of all ESRF patients. The clinical features at presentation were hypertension in 51 (59.3%), recurrent urinary tract infection (UTI) in 31 (36.1%), history of stones in 7 (8.1%), and gross hematuria in 4 (4.7%). Patients with history of recurrent UTI were more likely to be females (p < 0.01) and to present without renal failure (p < 0.05). Proteinuria > 1 g/day was significantly associated (p < 0.02) with hypertension at presentation. Patients who presented with renal failure were more likely to be males (p < 0.05), not to have history of recurrent UTI (p < 0.05), have proteinuria > 1 g/day (p < 0.02) and higher grades (grades IV and V) of reflux (p < 0.05). On logistic regression analysis, higher age of onset (odds ratio 4.6, p < 0.03), proteinuria > 1 g/day (odds ratio 3.8, p < 0.05), and male gender (odds ratio 3.5, p < 0.05) were significant risk factors for presentation for the first time with renal failure. The clinical features and course of VUR and RN as seen in India are different from those reported from elsewhere. The vast majority of patients in India are males and almost two thirds do not have a past history of UTI. Renal failure is present in more than three fourths of patients when a diagnosis of reflux is made and one third of all patients present with ESRD. Patients with a prior history of UTI are more commonly females and are less likely to have renal failure at presentation. Higher age of onset of symptoms, proteinuria > 1 g/day and male gender were risk factors for the development of renal failure. It is likely that these asymptomatic patients remain undetected during childhood, presenting late only after having incurred severe renal damage.

Mitomycin-C induced hemolytic uremic syndrome: a case report.

Mitomycin-C is used widely in the treatment of malignancies and is associated with serious dose related adverse effects including the occurrence of hemolytic uremic syndrome. We report a patient with a colonic adenocarcinoma who developed hemolytic uremic syndrome after receiving 85 mg/m2 of the drug. The patient was left untreated and died 5 months after this diagnosis was made, of a second malignancy. Differential diagnosis and treatment of this condition are discussed.

Novas formas de utilizaçäo terapêutica do hormônio do crescimento humano / New forms of therapeutic use of growth hormone in human

Com o advento da tenologia do RNA recombinante, a disponibilidade do crescimento humano (hGH) passou a ser ilimitado e o seu uso clínico está sendo investigado numa variedade de outras condiçoes clínicas diferentes do retardo de crescimento. A deficiência de GH em adultos com doenças hipofisárias caracteriza-se pela diminuiçao da massa magra, aumento relacionada ao hiper-somatotropismo. A administraçao de hGH por períodos de curta duraçao tem mostrado efeitos benéficos na composiçao corporal, ajustamento psico-social e capacidade funcional muscular em adultos deficientes de GH. Desde que as modificaçoes na composiçao corporal da seilidade sao semelhantes às da deficiência de GH e podem ser revertidas com o uso de hGH em doses substitutivas, tem sido postulado que a secreçao diminuída de GH observada na velhice pode contribuir para as alteraçoes geríatricas da composiçao corporal. Ainda nao se sabe se o tratamento com hGH a longo prazo melhorará o estado funcional da velhice sem causar complicaçoes. Estudos clínicos preliminares com crianças e adultos têm mostrado efeitos benéficos do hGH em diversas doenças associadas com o catabolismo protéico. Serao necessários, entretanto, estudos mais aprofundados e a mais longo prazo antes que a terapêutica com hGH possa a ser recomendada nessas condiçoes. (Arq Bras Endocrinol Metab 1994; 38/1:10-15).